Faculty Profiles - FUJIWARA Toshiyoshi

MISC - FUJIWARA Toshiyoshi

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Pseudohypoxia by HIF-PHD inhibitors activates tumor immune response for MSS colorectal cancer.

Toshiaki Ohara, Yuehua Chen, Yusuke Hamada, Hajime Kashima, Satoru Kikuchi, Kazuhiro Noma, Hiroshi Tazawa, Masayoshi Fujisawa, Toshiyoshi Fujiwara, Akihiro Matsukawa

CANCER SCIENCE 116 663 - 663 2025.1

Establishment of predictive biomarkers for carcinogenesis in ulcerative colitis using RNA editing analyses

Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Kaori Nitta, Fuminori Teraishi, Yuzo Umeda, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 84 ( 7 ) 2024.4

Pseudohypoxia by HIF-PHD inhibitors activates tumor immune response for MSS colorectal cancer

Toshiaki Ohara, Yuehua Chen, Yusuke Hamada, Seitaro Nishimura, Hotaka Kawai, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara, Akihiro Matsukawa

CANCER RESEARCH 84 ( 6 ) 2024.3

Cancer associated fibroblasts targeted photoimmunotherapy improves drug delivery

Seitaro Nishimura, Kazuhiro Noma, Tasuku Matsumoto, Tatsuya Takahashi, Yasushige Takeda, Hijiri Matsumoto, Tomoyoshi Kunitomo, Kento Kawasaki, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 84 ( 6 ) 2024.3

Surgical treatment of inflammatory bowel disease

近藤喜太, 金谷信彦, 森分和也, 重安邦俊, 藤原俊義, 藤原俊義, 藤原俊義, 藤原俊義

消化器外科 47 ( 3 ) 2024

難治性胃食道逆流症・食道裂孔ヘルニアに対する腹腔鏡手術によるQOL改善効果

田辺俊介, 野間和広, 河崎健人, 國友知義, 橋本将志, 賀島肇, 前田直見, 菊地覚次, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

cM1bリンパ節転移食道癌に対するコンバージョン手術の成績

前田直見, 野間和広, 河崎健人, 國友知義, 橋本将志, 賀島肇, 菊地覚次, 田辺俊介, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

頸部食道癌に対する喉頭温存に向けた取り組み

國友知義, 野間和広, 河崎健人, 橋本将志, 賀島肇, 前田直見, 菊地覚次, 田辺俊介, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

切除不能進行・再発食道癌に対する免疫チェックポイント阻害剤を用いた治療成績

河崎健人, 野間和広, 國友知義, 橋本将志, 賀島肇, 前田直見, 菊地覚次, 田辺俊介, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

ロボット支援食道癌手術の成績と課題

野間和広, 河崎健人, 國友知義, 橋本将志, 賀島肇, 前田直見, 菊地覚次, 白川靖博, 田辺俊介, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

術前DCF療法後の再発リスク因子と当院での術後補助療法の短期成績

橋本将志, 野間和広, 河崎健人, 國友知義, 賀島肇, 前田直見, 菊地覚次, 田辺俊介, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

ロボット食道癌手術導入後5年を経てその短期成績と長期成績

野間和広, 河崎健人, 國友知義, 橋本将志, 前田直見, 田辺俊介, 藤原俊義

日本ロボット外科学会学術集会プログラム・抄録集 16th 2024

超低肺機能の食道癌患者に対する術式と周術期管理の工夫

松本眞琴, 野間和広, 河崎健人, 國友知義, 橋本将志, 賀島肇, 前田直見, 田邊俊介, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

DCFとロボット支援下手術を駆使して挑むcT3br,cT4食道癌症例に対する挑戦

野間和広, 河崎健人, 國友知義, 橋本将志, 賀島肇, 前田直見, 菊地覚次, 田辺俊介, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

当院における高齢者食道癌の術後合併症の検討

高橋政史, 野間和広, 河崎健人, 國友知義, 橋本将志, 前田直見, 菊池覚次, 田辺俊介, 白川靖博, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 78th 2024

転移再発大腸癌の治療における臓器別アプローチおよびレジメン選択の工夫

重安邦俊, 高橋利明, 森分和也, 金谷信彦, 庄司良平, 松三雄騎, 近藤喜太, 寺石文則, 香川俊輔, 藤原俊義

大腸癌研究会プログラム・抄録集 101st 2024

食道癌機能温存手術の最新知見と手術手技 II.各論(手術手技)4)機能温存を重視した中下縦隔リンパ節郭清

野間和広, 田辺俊介, 藤原俊義

手術 78 ( 11 ) 2024

Team-based perioperative infection control for esophageal cancer patients in the era of robotic surgery and neoadjuvant DCF

田辺俊介, 野間和広, 松本聖, 國友知義, 田上幸憲, 橋本将志, 前田直見, 藤原俊義

日本外科感染症学会雑誌(Web) 21 ( 1 ) 2024

I 食道・胃 5 経裂孔アプローチによる食道胃接合部癌手術に必要な局所解剖

野間和広, 田辺俊介, 藤原俊義

手術 78 ( 4 ) 2024

Lynch症候群が疑われる進行大腸癌患者における術前化学療法と遺伝外来の実際

重安邦俊, 山本英喜, 岡田尚大, 半澤俊哉, 高橋利明, 深野智華, 二川摩周, 加藤芙美乃, 大住理沙, 平沢晃, 藤原俊義

日本遺伝性腫瘍学会学術集会プログラム・抄録集 30th 2024

Esophageal reconstruction with free jejunal flap

野間和広, 野間和広, 田邊俊介, 田邊俊介, 藤原俊義, 藤原俊義, 藤原俊義

消化器外科 46 ( 2 ) 2023

岡山大学消化器外科の大腸がん診療におけるがんゲノムプロファイリング検査の活用

重安邦俊, 香川俊輔, 寺石文則, 楳田祐三, 岡田尚大, 半澤俊哉, 橋本将志, 垣内慶彦, 松三雄騎, 菊地覚次, 黒田新士, 近藤喜太, 二宮貴一朗, 遠西大輔, 平沢晃, 藤原俊義

日本遺伝性腫瘍学会学術集会プログラム・抄録集 29th 2023

Double-surgeon techniqueの腹腔鏡下肝切除への応用

木村次郎, 藤智和, 高木弘誠, 木村裕司, 山田元彦, 楳田祐三, 藤原俊義

日本内視鏡外科学会総会(Web) 36th 2023

Soft pancreas症例に対するロボット支援下膵頭十二指腸切除術の有用性

藤智和, 高木弘誠, 楳田祐三, 木村裕司, 木村次郎, 山田元彦, 藤原俊義

日本内視鏡外科学会総会(Web) 36th 2023

ロボット支援下肝切除術におけるポート・機器セッティングのコツ

高木弘誠, 楳田祐三, 藤智和, 安井和也, 山田元彦, 木村裕司, 木村次郎, 藤原俊義

肝臓内視鏡外科研究会プログラム・抄録集 17th 2023

胃切除後患者に対する術後早期アミノ酸栄養と術後の継続した外来栄養指導によるサルコペニア予防

菊地覚次, 賀島肇, 松三雄騎, 山田元彦, 垣内慶彦, 黒田新士, 前田直見, 田辺俊介, 野間和宏, 藤原俊義

日本消化器外科学会雑誌(Web) 56 ( Supplement1 ) 2023

術前治療後の局所進行直腸癌に対するロボット支援下直腸手術の治療成績

寺石文則, 寺石文則, 山田元彦, 賀島肇, 垣内慶彦, 垣内慶彦, 松三雄騎, 重安邦俊, 重安邦俊, 近藤喜太, 黒田新士, 香川俊輔, 藤原俊義, 藤原俊義

日本ロボット外科学会学術集会プログラム・抄録集 15th 2023

ロボット支援下膵体尾部切除術における脾臓温存の意義と短期成績

山田元彦, 高木弘誠, 楳田祐三, 藤智和, 安井和也, 木村祐司, 木村次郎, 萱野真史, 廣野欣司, 佐藤真歩, 藤原俊義

日本膵切研究会プログラム・抄録集 50th 2023

ロボット支援下vs.開腹膵頭十二指腸切除術

高木弘誠, 楳田祐三, 藤智和, 安井和也, 木村裕司, 山田元彦, 木村次郎, 藤原俊義

日本膵切研究会プログラム・抄録集 50th 2023

ライフイベント時に本当に必要な支援とは?高いチーム力でダイバーシティとインクルージョンを目指す当院のキャリア支援

小林純子, 小林純子, 竹原裕子, 溝尾妙子, 菊地覚次, 菊地覚次, 三好健太郎, 三好健太郎, 黒田新士, 黒田新士, 田邊俊介, 田邊俊介, 楳田祐三, 楳田祐三, 小谷恭弘, 小谷恭弘, 杉本誠一郎, 杉本誠一郎, 岡崎幹生, 岡崎幹生, 枝園忠彦, 枝園忠彦, 豊岡伸一, 豊岡伸一, 藤原俊義, 藤原俊義, 笠原真悟, 笠原真悟

日本臨床外科学会雑誌 84 ( Supplement (Web) ) 2023

アスリート精神から学ぶ食道外科医育成のための教育法・自己研鑽法

田辺俊介, 野間和広, 河崎健人, 國友知義, 橋本将志, 加藤卓也, 前田直見, 重安邦俊, 菊地覚次, 黒田新士, 近藤喜太, 寺石文則, 楳田祐三, 白川靖博, 藤原俊義

日本臨床外科学会雑誌 84 ( Supplement (Web) ) 2023

胸腔鏡・腹腔鏡併用下に修復術を施行したMorgagni孔ヘルニアの1例

濱崎友洋, 野間和広, 河崎健人, 國友知義, 橋本将志, 加藤卓也, 前田直見, 菊地覚次, 黒田新士, 近藤喜太, 田辺俊介, 寺石文則, 楳田祐三, 白川靖博, 藤原俊義

日本内視鏡外科学会総会(Web) 36th 2023

術中体位の工夫でスムーズな手術進行が可能になった,胸部食道癌と右上葉肺癌の合併症例

安井雄一, 野間和広, 川崎健人, 國友知義, 橋本将志, 加藤卓也, 前田直見, 菊地覚次, 黒田新士, 近藤喜太, 田辺俊介, 寺石文則, 楳田祐三, 白川靖博, 藤原俊義

日本内視鏡外科学会総会(Web) 36th 2023

内腔突出型GISTに対するClosed-LECSの長期成績と胃癌への適応拡大

菊地覚次, 西崎正彦, 賀島肇, 黒田新士, 垣内慶彦, 田辺俊介, 前田直見, 野間和広, 香川俊輔, 楳田祐三, 藤原俊義

日本内視鏡外科学会総会(Web) 36th 2023

根治性と安全性の両立を目指した食道癌上縦隔リンパ節郭清定型化の工夫

白川靖博, 白川靖博, 桂佑貴, 澤田鉱幸, 石田道拡, 佐藤太祐, 丁田泰宏, 吉満政義, 中野敢友, 松川啓義, 井谷史嗣, 塩崎滋弘, 前田直見, 田辺俊介, 野間和広, 藤原俊義

日本内視鏡外科学会総会(Web) 36th 2023

Perioperative infection control in elderly esophageal cancer patients as a team effort

田辺俊介, 野間和広, 河崎健人, 國友知義, 橋本将志, 加藤卓也, 前田直見, 白川靖博, 藤原俊義

日本外科感染症学会雑誌(Web) 20 ( 3 ) 2023

胃切除後ロイシン強化経口栄養剤投与による術後体重減少抑制効果

菊地覚次, 高田暢夫, 賀島肇, 庄司良平, 松三雄騎, 垣内慶彦, 黒田新士, 田辺俊介, 前田直見, 野間和広, 藤原俊義

Gastroenterological Endoscopy (Web) 65 ( Supplement2 ) 2023

EDCシステムを使用した大腸悪性腫瘍登録の試み

高永都衣, 高永都衣, 高永都衣, 高永都衣, 高永都衣, 寺石文則, 寺石文則, 稲田涼, 松三雄騎, 松三雄騎, 庄司良平, 黒田新士, 黒田新士, 藤原俊義, 藤原俊義, 藤原俊義

日本診療情報管理学会学術大会抄録集 49th 2023

A new subtype of colorectal cancer based of RAS/RAF, micro-satellite status, and mesenchymal type for far-advanced CRC

矢野修也, 矢野修也, 重安邦俊, 谷岡洋亮, 山崎泰史, 河内麻里子, 平沢晃, 武田正, 香川俊輔, 藤原俊義, 永坂岳司

日本臨床腫瘍学会学術集会(CD-ROM) 19th 2022

Elucidation for the mechanism of lymph node metastasis of esophageal squamous cell carcinoma by extracellular vesicles

木谷嘉孝, 吉岡祐亮, 賀島肇, 野間和広, 田澤大, 田澤大, 藤原俊義, 永川裕一, 落谷孝広

日本癌学会学術総会抄録集(Web) 81st 2022

Minimally invasive approach for gastric tumors depending on the characteristics or location of tumor

菊地覚次, 西崎正彦, 神崎洋光, 黒田新士, 田辺俊介, 野間和広, 楳田祐三, 岡田裕之, 藤原俊義

日本消化管学会雑誌(CD-ROM) 6 ( Supplement (CD-ROM) ) 2022

家族性大腸腺腫症における2チームでの経肛門的直腸間膜切除術(Trans anal Total Mesorectal Excision:TaTME)を用いた大腸全摘

重安邦俊, 武田正, 近藤喜太, 寺石文則, 二川摩周, 加藤芙美乃, 十川麗美, 堀口繁, 香川俊輔, 平沢晃, 藤原俊義

日本遺伝性腫瘍学会学術集会プログラム・抄録集 28th 2022

患者参加型継続的栄養指導による胃癌術後のサルコペニア予防効果

菊地覚次, 高田暢夫, 黒田新士, 田辺俊介, 前田直見, 賀島肇, 垣内慶彦, 野間和広, 香川俊輔, 高橋絢子, 楳田祐三, 四方賢一, 四方賢一, 藤原俊義

日本癌治療学会学術集会(Web) 60th 2022

ペムブロリズマブ使用中に下垂体機能低下症と間質性肺炎を発症したが診療科横断的に加療できた高頻度マイクロサテライト不安定性大腸癌の1例

重安邦俊, 矢野修也, 武田正, 山崎泰史, 河内麻里子, 平沢晃, 香川俊輔, 藤原俊義

日本臨床腫瘍学会学術集会(CD-ROM) 19th 2022

当施設におけるロボット支援下直腸手術の導入と短期治療成績

寺石文則, 寺石文則, 中村峻輔, 高橋一剛, 武田正, 垣内慶彦, 重安邦俊, 重安邦俊, 近藤喜太, 黒田新士, 野間和広, 香川俊輔, 香川俊輔, 藤原俊義, 藤原俊義

日本ロボット外科学会学術集会プログラム・抄録集 14th 2022

多系統萎縮症(Shy-Drager症候群)を基礎疾患に有する患者に発症した逆行性腸重積の1例

伊木道子, 垣内慶彦, 庄司良平, 新田薫, 近藤喜太, 黒田新士, 香川俊輔, 藤原俊義

日本臨床外科学会雑誌 83 ( Supplement (Web) ) 2022

Oncolytic virus-mediated p53 gene therapy enhances anti-tumor immunity against peritoneal metastasis of gastric cancer

Motoyasu Tabuchi, Satoru Kikuchi, Toshihiro Ogawa, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Junko Ohtsuka, Rieko Ohki, Yasuo Urata, Toshiyoshi Fujiwara

CANCER SCIENCE 112 426 - 426 2021.2

Oncolytic virus-mediated p53 overexpression interrupts tumor-stromal network in pancreatic tumor microenvironment

Takeyoshi Nishiyama, Hiroshi Tazawa, Yoshinori Kajiwara, Ryohei Shoji, Satoru Kikuchi, Shinji Kuroda, Kazuhiro Noma, Ryuichi Yoshida, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 112 440 - 440 2021.2

Gemcitabine-resistant pancreatic ductal adenocarcinoma cells promote immunosuppressive tumor microenvironment

Yoshinori Kajiwara, Hiroshi Tazawa, Takeyoshi Nishiyama, Ryohei Shoji, Takuro Fushimi, Satoru Kikuchi, Shinji Kuroda, Kazuhiro Noma, Ryuichi Yoshida, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 112 560 - 560 2021.2

消化器系遺伝性腫瘍のスクリーニングとサーベイランスのための早期介入プログラムの構築

重安邦俊, 武田正, 矢野修也, 二川摩周, 山本英喜, 近藤喜太, 寺石文則, 香川俊輔, 平沢晃, 藤原俊義

日本外科学会定期学術集会(Web) 121st 2021

診療科横断的な遺伝性大腸癌診療体制の構築

重安邦俊, 武田正, 矢野修也, 二川摩周, 加藤芙美乃, 十川麗美, 山本英喜, 香川俊輔, 平沢晃, 藤原俊義

日本遺伝性腫瘍学会学術集会プログラム・抄録集 27th 2021

BRCA1およびSMAD4に病的バリアントを認めた一家系

加藤芙美乃, 山本英喜, 山本英喜, 坂井美佳, 坂井美佳, 河内麻里子, 河内麻里子, 二川摩周, 十川麗美, 間森智加, 笹原麻子, 重安邦俊, 香川俊輔, 藤原俊義, 土井原博義, 平沢晃, 平沢晃

日本遺伝性腫瘍学会学術集会プログラム・抄録集 27th 2021

ハイリスク高齢者大腸癌への周術期管理チーム介入による術後アウトカムの変化

寺石文則, 垣内慶彦, 武田正, 重安邦俊, 矢野修也, 近藤喜太, 香川俊輔, 藤原俊義

日本外科学会定期学術集会(Web) 121st 2021

Treatment for colorectal liver metastasis: evolving paradigms and future perspectives

楳田祐三, 田澤大, 矢野修也, 重安邦俊, 神崎洋光, 寺石文則, 黒田新士, 香川俊輔, 八木孝仁, 平沢晃, 岡田裕之, 藤原俊義

日本がん転移学会学術集会・総会プログラム抄録集 30th 2021

高齢者pStageIII大腸癌の予後と転帰から術後化学療法について考察する

寺石文則, 成田周平, 武田正, 垣内慶彦, 重安邦俊, 矢野修也, 近藤喜太, 野間和広, 楳田祐三, 香川俊輔, 藤原俊義

大腸癌研究会プログラム・抄録集 95th 2021

局所進行直腸癌に対する術前CAPOX+RT療法の治療成績

武田正, 寺石文則, 坂本真樹, 重安邦俊, 矢野修也, 近藤喜太, 黒田新士, 香川俊輔, 藤原俊義

大腸癌研究会プログラム・抄録集 94th 2021

直腸癌の同時性肝転移と肺転移症例における原発巣の臨床病理学的特徴の比較

重安邦俊, 武田正, 矢野修也, 近藤喜太, 寺石文則, 香川俊輔, 藤原俊義

大腸癌研究会プログラム・抄録集 94th 2021

再発直腸癌に対する腹腔鏡下骨盤内臓全摘術への蛍光ガイド下手術

矢野修也, 矢野修也, 近藤喜太, 重安邦俊, 寺石文則, 武田正, 坂本真樹, 菊地覚次, 黒田新士, 香川俊輔, 藤原俊義

大腸癌研究会プログラム・抄録集 94th 2021

ロボット支援下膵頭十二指腸切除術の安全な導入と術式の定型化

高木弘誠, 楳田祐三, 吉田龍一, 杭瀬崇, 吉田一博, 安井和也, 八木孝仁, 藤原俊義

日本外科学会定期学術集会(Web) 121st 2021

R/BR膵癌術前化学療法施行症例における術直前CA19-9値の意義に関する検討

安井和也, 吉田龍一, 楳田祐三, 杭瀬崇, 吉田一博, 高木弘誠, 八木孝仁, 藤原俊義

日本外科学会定期学術集会(Web) 121st 2021

進行胆嚢癌に対する外科治療-手術成績を踏まえ,その限界を考える-

吉田一博, 楳田祐三, 吉田龍一, 杭瀬崇, 安井和也, 高木弘誠, 荒木宏之, 谷悠真, 實金悠, 八木孝仁, 藤原俊義

日本外科学会定期学術集会(Web) 121st 2021

食道癌周術期管理における早期介入の有用性岡山大学病院におけるPERiOの取り組み

野間和広, 最所公平, 前田直見, 田辺俊介, 白川靖博, 白川靖博, 藤原俊義

外科と代謝・栄養 55 ( 4 ) 2021

p53発現による線維性微小環境の再プログラム化は膵臓癌における腫瘍融解ウイルス療法の治療効果を増強する

西山岳芳, 田澤大, 田澤大, 梶原義典, 庄司良平, 永井康雄, 菊地覚次, 黒田新士, 黒田新士, 野間和広, 吉田龍一, 西崎正彦, 田中啓祥, 狩野光伸, 浦田泰生, 香川俊輔, 藤原俊義

日本癌学会学術総会抄録集(Web) 80th 2021

頭頚部癌集学的治療に対する胃瘻を有効に活用した栄養管理確立への道のり

田辺俊介, 田辺俊介, 今井祥子, 今井祥子, 開原裕子, 開原裕子, 長谷川祐子, 長谷川祐子, 岡野寛子, 岡野寛子, 大木晴美, 大木晴美, 三浦太郎, 三浦太郎, 金聖暎, 金聖暎, 前田直見, 前田直見, 菊地覚次, 菊地覚次, 野間和広, 白川靖博, 四方賢一, 四方賢一, 藤原俊義

学会誌JSPEN(Web) 3 ( Supplement 1 ) 2021

進化する外科マネージメントセンターそれぞれの夢を実現するためのキャリアパス支援システム

菊地覚次, 黒田新士, 吉田龍一, 香川俊輔, 山根正修, 小谷恭弘, 笠原真悟, 豊岡伸一, 藤原俊義

日本外科学会定期学術集会抄録集 120回 SP - 8 2020.8

地域枠医師に対する外科専門研修のあり方充実した地域医療の実現を目指して

黒田新士, 吉田龍一, 池田宏国, 岡崎幹生, 大澤晋, 小谷恭弘, 山根正修, 杉本誠一郎, 菊地覚次, 安井和也, 野田卓男, 笠原真悟, 豊岡伸一, 土井原博義, 藤原俊義

日本外科学会定期学術集会抄録集 120回 SP - 4 2020.8

A phase II study of FOLFOXIRI plus bevacizumab (Bmab) as initial chemotherapy for patients (pts) with untreated metastatic colorectal cancer (mCRC): TRICC1414 (Be TRI)

Takeshi Yamada, Tomohiro Nishina, Junichiro Nasu, Toshihiko Matsumoto, Yasuhiro Yuasa, Takeshi Shiraishi, Hiroaki Nagano, Ichiro Moriyama, Toshiyoshi Fujiwara, Masashi Miguchi, Ryosuke Yoshida, Kimiyasu Nosaka, Hiroaki Tanioka, Takeshi Nagasaka, Yasuro Kurisu, Michiya Kobayashi, Kenji Tsuchihashi, Michio Inukai, Takashi Kikuchi, Katsunori Shinozaki

JOURNAL OF CLINICAL ONCOLOGY 38 ( 4 ) 2020.2

RNA editing activated by chemoradiation therapy artificially generates neoantigen in colorectal cancer

小松泰浩, 重安邦俊, 重安邦俊, 武田正, 高橋一剛, 畑七々子, 吉田一博, 矢野修也, 矢野修也, 大原利章, 野間和広, 楳田祐三, 黒田新士, 黒田新士, 近藤喜太, 寺石文則, 寺石文則, 田澤大, 香川俊輔, 香川俊輔, 藤原俊義

日本癌学会学術総会抄録集(Web) 79th 2020

希少MSI-H大腸癌患者由来組織片を用いたマウスモデル(PDX)による擬似クローン化の試み

矢野修也, 矢野修也, 重安邦俊, 三村直毅, 岸本浩行, 母里淑子, 黒田新士, 近藤喜太, 寺石文則, 香川俊輔, 平沢晃, 藤原俊義

日本遺伝性腫瘍学会学術集会プログラム・抄録集 26th 2020

ペムブロリズマブ使用中に下垂体機能低下症を来たしステロイド投与が著効した高頻度マイクロサテライト不安定性大腸癌の1例

重安邦俊, 岸本浩行, 母里淑子, 武田正, 矢野修也, 黒田新士, 近藤喜太, 寺石文則, 香川俊輔, 平沢晃, 藤原俊義

日本遺伝性腫瘍学会学術集会プログラム・抄録集 26th 2020

Reversible EMT-MET biosensor-mediated imaging visualizes inducible resistance to chemotherapy with hybrid E/M phase

三村直毅, 矢野修也, 矢野修也, 田澤大, 家田偉史, 岡林大樹, 重安邦俊, 重安邦俊, 武田正, 吉田一博, 寺石文則, 寺石文則, 楳田祐三, 香川俊輔, 香川俊輔, 藤原俊義

日本癌学会学術総会抄録集(Web) 79th 2020

Perspective and prospective of RNA editing in colorectal cancer microenvironme

武田正, 重安邦俊, 重安邦俊, 小松泰浩, 高橋一剛, 畑七々子, 吉田一博, 矢野修也, 矢野修也, 近藤喜太, 寺石文則, 寺石文則, 楳田祐三, 田澤大, 香川俊輔, 香川俊輔, 藤原俊義

日本癌学会学術総会抄録集(Web) 79th 2020

Development of novel photoimmunotherapy targeting cancer associated fibroblasts.

小林照貴, 野間和広, 河崎健人, 赤井正明, 西脇紀之, 大原利章, 田澤大, 藤原俊義

日本癌学会学術総会抄録集(Web) 79th 2020

癌微小環境が引き起こす腫瘍免疫抑制の解明“Drug repositioning′′による免疫応答賦活化の可能性

西脇紀之, 野間和広, 赤井正明, 小林照貴, 鳴坂徹, 河本慧, 加藤卓也, 前田直見, 田辺俊介, 大原利章, 田澤大, 白川靖博, 藤原俊義

日本外科学会定期学術集会(Web) 120th 2020

新世代の外科医の苦悩と挑戦

西脇紀之, 野間和広, 赤井正明, 小林照貴, 鳴坂徹, 河本慧, 大原利章, 田澤大, 藤原俊義

日本外科学会定期学術集会(Web) 120th 2020

Fibroblast activation protein-α(FAP)を標的とした癌関連線維芽細胞(CAFs)に対する光免疫療法~Sunrise of targeting tumor microenvironment therapy~

小林照貴, 野間和広, 赤井正明, 西脇紀之, 鳴坂徹, 河本慧, 前田直見, 大原利章, 田辺俊介, 田澤大, 白川靖博, 藤原俊義

日本外科学会定期学術集会(Web) 120th 2020

Interplay between gastric cancer subtypes and cancer-associated fibroblasts

李云成, 田澤大, 野間和広, 大原利章, 黒田新士, 黒田新士, 菊地覚次, 菊地覚次, 香川俊輔, 香川俊輔, 藤原俊義

日本癌学会学術総会抄録集(Web) 79th 2020

Overcoming cancer-associated fibroblasts induced immunosuppression by blocking IL-6-Exploring for Drug Repositioning-

西脇紀之, 野間和広, 大原利章, 小林照貴, 菊地覚次, 菊地覚次, 田澤大, 藤原俊義

日本癌学会学術総会抄録集(Web) 79th 2020

鼠径ヘルニア術後の難治性疼痛およびACNESに対する神経切離術の経験

近藤喜太, 垣内慶彦, 矢野修也, 武田正, 重安邦俊, 菊地覚次, 黒田新士, 寺石文則, 香川俊輔, 藤原俊義

日本ヘルニア学会学術集会抄録集(CD-ROM) 18th 2020

CDDP+VP-16療法を根治術後に施行し長期無再発生存している十二指腸乳頭部MANECの1例

谷悠真, 杭瀬崇, 堀口繁, 實金悠, 荒木宏之, 高木弘誠, 安井和也, 吉田一博, 吉田龍一, 楳田祐三, 八木孝仁, 藤原俊義

日本癌治療学会学術集会(Web) 58th 2020

局所進行切除不能膵癌conversion surgeryにおける結腸動脈を用いた肝動脈再建

吉田龍一, 楳田祐三, 杭瀬崇, 吉田一博, 安井和也, 高木弘誠, 荒木宏之, 八木孝仁, 藤原俊義

日本膵切研究会プログラム・抄録集 47th 2020

The Six National University Consortium in Liver Transplant Professionals Training Program (SNUC-LT Program) in Japan: Experiences as a trainee

高木弘誠, 杭瀬崇, 楳田祐三, 藤原俊義, 八木孝仁

移植(Web) 55 ( 4 ) 2020

胃が使用不可能な場合の空腸を用いた食道再建の工夫

白川靖博, 野間和広, 前田直見, 田辺俊介, 櫻間教文, 藤原俊義

日本胸部外科学会定期学術集会(Web) 73rd 2020

A novel photoimmunotherapy for cancer cells and cancer-associated-fibroblasts

小林照貴, 野間和広, 大原利章, 河崎健人, 赤井正明, 西脇紀之, 前田直見, 菊地覚次, 矢野修也, 田辺俊介, 田澤大, 白川靖博, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 31st 2020

食道癌根治手術10年後に発症した肝転移を伴うStageIV胃管癌の一治療例

田辺俊介, 野間和広, 前田直見, 白川靖博, 藤原俊義

日本胸部外科学会定期学術集会(Web) 73rd 2020

生体肝移植後に発症した食道癌の一治療例

田辺俊介, 野間和広, 前田直見, 白川靖博, 藤原俊義

日本胸部外科学会定期学術集会(Web) 73rd 2020

食道癌手術における臨床応用解剖実習の現状と展望

前田直見, 白川靖博, 田辺俊介, 野間和広, 櫻間教文, 藤原俊義

日本胸部外科学会定期学術集会(Web) 73rd 2020

保存的に治癒し得た食道癌胸骨後経路再建術後に発症した胃管気管瘻の一例

西村星多郎, 白川靖博, 菅野令子, 光井恵麻, 國友知義, 前田直見, 田邊俊介, 野間和広, 櫻間教文, 藤原俊義

日本臨床外科学会雑誌 81 2020

T4bに対する導入DCF-RT療法~高い局所制御率とその課題~

橋本将志, 白川靖博, 前田直見, 田邊俊介, 櫻間教文, 野間和広, 西崎正彦, 勝井邦彰, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 74th 2020

再手術症例から学ぶ形成外科的手技を用いた合併症回避のための術式の工夫

松本洋, 太田智之, 川本幸司, 木股敬裕, 白川靖博, 野間和広, 田邊俊介, 前田直見, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 74th 2020

食道胃接合部癌の術式選択

野間和広, 白川靖博, 白川靖博, 藤原俊義

日本消化器外科学会雑誌(Web) 53 ( Supplement2 ) 2020

Activation of AZIN1 RNA editing facilitates and promotes invasive potential of cancer associated fibroblasts in colorectal cancer

Sho Takeda, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Kazuhiro Yoshida, Yoshiko Mori, Shuya Yano, Kazuhiro Noma, Yuzo Umeda, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Hiroshi Tazawa, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

CANCER RESEARCH 79 ( 13 ) 2019.7

Boosting replication and penetration of telomerase-specific replicative virus by paclitaxel induces synthetic lethality in peritoneal metastasis of gastric cancer

Toshihiro Ogawa, Satoru Kikuchi, Wataru Ishikawa, Hiroshi Tazawa, Motoyasu Tabuchi, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

CANCER RESEARCH 79 ( 13 ) 2019.7

Sternness control by iron chelator is a novel therapeutic strategy for esophageal cancer

Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Noriyuki Nishiwaki, Motoyasu Tabuchi, Takuro Fushimi, Toshihiro Ogawa, Sho Takeda, Satoshi Komoto, Hiroaki Sato, Satoru Kikuchi, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 79 ( 13 ) 2019.7

Overcoming resistance of conventional therapies by targeting cancer-associated fibroblasts (CAFs) with near-infrared photoimmunotherapy (NIR-PIT)

Satoshi Komoto, Kazuhiro Noma, Ryoichi Katsube, Takuya Kato, Toshiaki Ohara, Hiroaki Sato, Toru Narusaka, Noriyuki Nisiwaki, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 79 ( 13 ) 2019.7

Endoscopic intratumoral injection of OBP-301 (telomelysin) with radiotherapy in esophageal cancer patients unfit for standard treatments.

Shunsuke Tanabe, Hiroshi Tazawa, Nobuhiko Kanaya, Kazuhiro Noma, Shunsuke Kagawa, Shinji Kuroda, Yasuo Urata, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

JOURNAL OF CLINICAL ONCOLOGY 37 ( 4 ) 2019.2

小腸腺癌2症例の治療経験

母里淑子, 近藤喜太, 重安邦俊, 小松泰造, 三村直毅, 戸嶋俊明, 矢野修也, 岸本浩行, 寺石文則, 香川俊輔, 藤原俊義

日本大腸肛門病学会雑誌(Web) 72 ( 5 ) 2019

Fluorescence-guided novel therapeutic strategy for therapy-refractory tumor cells identified by cell cycle imaging

矢野修也, 矢野修也, 田澤大, 重安邦俊, 香川俊輔, 藤原俊義

日本癌学会学術総会抄録集(Web) 78th 2019

StageIV大腸癌における腫瘍占拠部位別の予後の検討

寺石文則, 寺石文則, 公文剣斗, 戸嶋俊明, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 浅野博昭, 岸本浩行, 稲田涼, 尾崎和秀, 志摩泰生, 西岡豊, 藤原俊義

日本大腸肛門病学会雑誌(Web) 72 ( 5 ) 2019

T1大腸癌手術症例の病理組織学的特徴と予後の検討

寺石文則, 戸嶋俊明, 重安邦俊, 母里淑子, 矢野修也, 近藤喜太, 岸本浩行, 藤原俊義

日本大腸肛門病学会雑誌(Web) 72 ( 5 ) 2019

RNA編集とマイクロサテライト不安定性の関連および免疫療法に与える影響について

重安邦俊, 武田正, 小松泰浩, 母里淑子, 矢野修也, 近藤喜太, 寺石文則, 香川俊輔, 藤原俊義

日本家族性腫瘍学会学術集会プログラム・抄録集 25th 2019

同時性肝転移を有する大腸癌症例における原発巣切除の意義

寺石文則, 藤本卓也, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 香川俊輔, 尾崎和秀, 藤原俊義

大腸癌研究会プログラム・抄録集 91st 2019

Multiple gastrointestinal stromal tumors of the small intestine in a patient with neurofibromatosis type 1: a case report

母里淑子, 重安邦俊, 吉岡貴裕, 永坂岳司, 原賀順子, 香川俊輔, 寺石文則, 豊岡伸一, 平沢晃, 藤原俊義

家族性腫瘍(Web) 19 ( 2 ) 2019

周術期管理チーム介入によるリスク評価が高齢者大腸癌患者の術後アウトカムに与える影響

寺石文則, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 藤原俊義, 藤原俊義

日本消化器外科学会雑誌(Web) 52 ( Supplement2 ) 2019

Effect of an enhanced recovery after surgery protocol in patients undergoing pancreaticoduodenectomy: A randomized controlled trial

高木弘誠, 吉田龍一, 八木孝仁, 楳田祐三, 信岡大輔, 杭瀬崇, 樋之津史郎, 松崎孝, 森松博史, 江口潤, 和田淳, 千田益生, 藤原俊義

学会誌JSPEN(Web) 1 ( Supplement ) 2019

術前化学療法を行った頸胸境界部食道癌の治療成績

橋本将志, 白川靖博, 梅田将志, 小林照貴, 前田直見, 田邊俊介, 野間和広, 楳田祐三, 藤原俊義

日本消化器外科学会雑誌(Web) 52 ( Supplement1 ) 2019

Minimally invasive telomerase-targeted molecular therapy in esophageal cancer patients unfit for standard treatments

田澤大, 田澤大, 田辺俊介, 野間和広, 黒田新士, 黒田新士, 香川俊輔, 香川俊輔, 浦田泰生, 白川靖博, 藤原俊義

日本癌学会学術総会抄録集(Web) 78th 2019

食道癌に対する鏡視下手術導入による周術期管理の変遷と多職種介入による外科感染対策の現況

田辺俊介, 白川靖博, 前田直見, 野間和広, 藤原俊義

日本外科感染症学会雑誌(Web) 16 ( 5 ) 2019

心負荷軽減の観点からみた混合型食道裂孔ヘルニア手術の新たな手術適応と手術手技の工夫

田邊俊介, 白川靖博, 梅田将志, 橋本将志, 小林照貴, 前田直見, 櫻間教文, 野間和広, 楳田祐三, 藤原俊義

日本消化器外科学会雑誌(Web) 52 ( Supplement1 ) 2019

高度食道裂孔ヘルニア手術における心負荷に着目した新たな手術適応と手術手技の工夫

田辺俊介, 白川靖博, 前田直見, 野間和広, 藤原俊義

日本ヘルニア学会学術集会抄録集(CD-ROM) 17th 2019

食道癌周術期管理におけるPERiOの現況とエビデンス創出に向けた課題

田辺俊介, 白川靖博, 前田直見, 野間和広, 藤原俊義

日本胸部外科学会定期学術集会(Web) 72nd 2019

食道領域cadaver surgical trainingの取り組みについて

白川靖博, 前田直見, 田辺俊介, 野間和広, 藤原俊義

日本胸部外科学会定期学術集会(Web) 72nd 2019

Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer crosstalk

Hiroshi Tazawa, Takeshi Ieda, Shuya Yano, Kunitoshi Shigeyasu, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara

CANCER SCIENCE 109 669 - 669 2018.12

Novel virotherapy for scirrhous gastric cancer with peritoneal metastasis

Wataru Ishikawa, Satoru Kikuchi, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 761 - 761 2018.12

Dual-targeting Photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in tumor microenvironment

Hiroaki Sato, Kazuhiro Noma, Toru Narusaka, Satoshi Komoto, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 371 - 371 2018.12

Stemness control by iron chelator is a novel strategy for cancer treatment

Toshiaki Ohara, Yuki Katsura, Kazuhiro Noma, Toru Narusaka, Hiroaki Sato, Satoshi Komoto, Takuya Kato, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 1309 - 1309 2018.12

Near-infrared photoimmunotherapy using anti-GD2 antibody-photosensitizer conjugate for neuroblastoma

Hiroshi Nouso, Hiroshi Tazawa, Terutaka Tanimoto, Morimochi Tani, Takanori Oyama, Hiroaki Sato, Kazuhiro Noma, Shunsuke Kagawa, Hisataka Kobayashi, Takuo Noda, Toshiyoshi Fujiwara

CANCER SCIENCE 109 1140 - 1140 2018.12

Oncolytic virotherapy for inhibition of epithelial- mesenchymal transition in esophageal cancer

Tomoya Masuda, Hiroshi Tazawa, Takeshi Ieda, Yuuri Hashimoto, Shunsuke Tanabe, Kazuhiro Noma, Yasuo Urata, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 868 - 868 2018.12

Cancer-associated fibroblasts affect the intra-tumoral infiltration of CD8+and FoxP3+T cells via IL-6

Takuya Kato, Kazuhiro Noma, Hiroaki Sato, Satoshi Komoto, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 1120 - 1120 2018.12

Novel theranostic strategy against peritoneal metastasis of scirrhous gastric cancer: Combination with fluorescence oncolytic adenovirus and chemotherapy

Wataru Ishikawa, Satoru Kikuchi, Hiroshi Tazawa, Toshiaki Ohara, Shinji Kuroda, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 78 ( 13 ) 2018.7

Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer network in vitro and in vivo

Hiroshi Tazawa, Takeshi Ieda, Shuya Yano, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara

CANCER RESEARCH 78 ( 13 ) 2018.7

Dual-targeting photoimmunotherapy (NIR-PIT) for esophageal cancer cells and cancer-associated fibroblasts (CAFs)

Hiroaki Sato, Kazuhiro Noma, Toru Narusaka, Satoshi Komoto, Yuki Katsura, Takuya Kato, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

CANCER RESEARCH 78 ( 13 ) 2018.7

Iron depletion suppress the stemness markers and functions of cancer stem cells

Toshiaki Ohara, Yuki Katsura, Kazuhiro Noma, Toru Narusaka, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Yasuko Tomono, Takayuki Ninomiya, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 78 ( 13 ) 2018.7

Development of near-infrared photoimmunotherapy targeting GD2-positive neuroblastoma

Hiroshi Nouso, Hiroshi Tazawa, Terutaka Tanimoto, Morimichi Tani, Takanori Oyama, Hiroaki Sato, Kazuhiro Noma, Shunsuke Kagawa, Hisataka Kobayashi, Takuo Noda, Toshiyoshi Fujiwara

CANCER RESEARCH 78 ( 13 ) 2018.7

Transforming growth factor-b-induced epithelial-mesenchymal transition is attenuated by telomerase-specific oncolytic virotherapy in human esophageal cancer

Tomoya Masuda, Hiroshi Tazawa, Takeshi Ieda, Yuuri Hashimoto, Shunsuke Tanabe, Kazuhiro Noma, Yasuo Urata, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 78 ( 13 ) 2018.7

Cancer-associated fibroblasts regulate intratumoral CD8(+)/FoxP3(+) T cells via interleukin 6 in the tumor immune microenvironment

Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hiroaki Sato, Satoshi Kohmoto, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Masaru Inagaki, Toshiyoshi Fujiwara

CANCER RESEARCH 78 ( 13 ) 2018.7

【膵癌に挑む】膵癌に対するウイルス療法の実用化に向けて

國府島健, 田澤大, 杭瀬崇, 吉田龍一, 楳田祐三, 藤原俊義

消化器外科 41 ( 6 ) 931 - 938 2018.5

腫瘍融解ウイルス併用放射線療法による食道癌治療成績向上への取り組み

田辺俊介, 白川靖博, 前田直見, 二宮卓之, 黒田新士, 野間和広, 楳田祐三, 田澤大, 香川俊輔, 藤原俊義

日本外科学会定期学術集会抄録集 118回 944 - 944 2018.4

A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study)

Shunsuke Kagawa, Atsushi Muraoka, Takeshi Kambara, Hiroshi Nakayama, Ryosuke Hamano, Norimitsu Tanaka, Kazuhiro Noma, Kohji Tanakaya, Hiroyuki Kishimoto, Kunitoshi Shigeyasu, Shinji Kuroda, Satoru Kikuchi, Kazuya Kuwada, Masahiko Nishizaki, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Cancer Chemotherapy and Pharmacology 81 ( 2 ) 387 - 392 2018.2

Language：English Publisher：Springer Verlag

Background: Trastuzumab when combined with fluoropyrimidine and cisplatin was proven to improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) in the ToGA study. The safety and efficacy of trastuzumab in combination with docetaxel and S-1 have not yet been evaluated. Methods: This study was a multicenter, phase II study. Patients with chemotherapy-naïve HER2-positive advanced or metastatic GC were eligible. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 and 6 mg/kg in subsequent cycles. Docetaxel was administered intravenously at 40 mg/m2 on day 1 of each cycle. S-1 was administered at a dosage based on body surface area for 14 days in a 3-weekly cycle. The primary endpoint was progression-free survival (PFS). Results: A total of 23 patients were enrolled. Median PFS was 6.7 months (95% CI 4.1–10.1). The response rate (RR) was 39.1%. Median overall survival (OS) and time to treatment failure (TTF) were 17.5 and 4.4 months, respectively. Major grade 3–4 adverse events were neutropenia (39.1%), leukopenia (30.4%), and febrile neutropenia (8.7%). Conclusion: Trastuzumab in combination with docetaxel and S-1 showed effective antitumor activity and manageable toxicities as first-line treatment for patients with HER2-positive GC.

DOI： 10.1007/s00280-017-3505-4

Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer

Mariko Kochi, Takayuki Iwamoto, Naoki Niikura, Giampaolo Bianchini, Shinobu Masuda, Taeko Mizoo, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Yutaka Tokuda, Hiroyoshi Doihara, Junji Matsuoka, Toshiyoshi Fujiwara

Breast Cancer Research and Treatment 167 ( 1 ) 39 - 47 2018.1

Language：English Publisher：Springer New York LLC

Purpose: The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes. Methods: We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies. Results: Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P &lt
0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30–3.14, P = 0.025). Conclusions: TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.

DOI： 10.1007/s10549-017-4502-3

Molecular radiosensitization of p53-armed telomerase-dependent oncolytic adenovirus against human soft-tissue sarcoma

Tadashi Komatsubara, Hiroshi Tazawa, Yusuke Mochizuki, Kazuhisa Sugiu, Toshinori Omori, Yasuaki Yamakawa, Syuhei Osaki, Joe Hasei, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

CANCER SCIENCE 109 454 - 454 2018.1

Detection of circulating tumor cells in cervical cancer using a conditionally replicative adenovirus targeting telomerase-positive cells. International journal

Masahiro Takakura, Takeo Matsumoto, Mitsuhiro Nakamura, Yasunari Mizumoto, Subaru Myojyo, Rena Yamazaki, Jyunpei Iwadare, Yukiko Bono, Shunsuke Orisaka, Takeshi Obata, Takashi Iizuka, Kyosuke Kagami, Kentaro Nakayama, Hideki Hayakawa, Fuminori Sakurai, Hiroyuki Mizuguchi, Yasuo Urata, Toshiyoshi Fujiwara, Satoru Kyo, Toshiyuki Sasagawa, Hiroshi Fujiwara

Cancer science 109 ( 1 ) 231 - 240 2018.1

Language：English

Circulating tumor cells (CTC) are newly discovered biomarkers of cancers. Although many systems detect CTC, a gold standard has not yet been established. We analyzed CTC in uterine cervical cancer patients using an advanced version of conditionally replicative adenovirus targeting telomerase-positive cells, which was enabled to infect coxsackievirus-adenovirus receptor-negative cells and to reduce false-positive signals in myeloid cells. Blood samples from cervical cancer patients were hemolyzed and infected with the virus and then labeled with fluorescent anti-CD45 and anti-pan cytokeratin antibodies. GFP (+)/CD45 (-) cells were isolated and subjected to whole-genome amplification followed by polymerase chain reaction analysis of human papillomavirus (HPV) DNA. CTC were detected in 6 of 23 patients with cervical cancers (26.0%). Expression of CTC did not correlate with the stage of cancer or other clinicopathological factors. In 5 of the 6 CTC-positive cases, the same subtype of HPV DNA as that of the corresponding primary lesion was detected, indicating that the CTC originated from HPV-infected cancer cells. These CTC were all negative for cytokeratins. The CTC detected by our system were genetically confirmed. CTC derived from uterine cervical cancers had lost epithelial characteristics, indicating that epithelial marker-dependent systems do not have the capacity to detect these cells in cervical cancer patients.

DOI： 10.1111/cas.13449

Novel evidence for AZIN1 RNA editing-mediated oncogenic role in colorectal cancer

Kunitoshi Shigeyasu, Sho Takeda, Yoshinaga Okugawa, Yuji Toiyama, Takeshi Nagasaka, Hiroshi Tazawa, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

CANCER SCIENCE 109 529 - 529 2018.1

Focusing on the antitumor effect of iron chelator, specifically suppressing the stemness of cancer stem cell.

Yuki Katsura, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Takayuki Ninomiya, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 87 - 87 2018.1

Cancer-associated fibroblasts (CAFs) promote to tumor immunosuppression via IL-6 secretion.

Takuya Kato, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 299 - 299 2018.1

Novel theranostic strategy: combination of fluorescence oncolytic virus and chemotherapy for scirrhous gastric cancer

Wataru Ishikawa, Satoru Kikuchi, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 912 - 912 2018.1

Fluorescence-guided live cell imaging system of EMT-tumor microenvironment network in gastrointestinal cancer

Takeshi Ieda, Hiroshi Tazawa, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Takeshi Imamura, Toshiyoshi Fujiwara

CANCER SCIENCE 109 557 - 557 2018.1

Liposomally formulated indocyanine green derivative encapsulating anticancer drugs for photoinduced immunotherapy

Tetsuya Kagawa, Hiroyuki Kishimoto, Yuki Matsumi, Hiroshi Tazawa, Toshiaki Ohara, Takeshi Nagasaka, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 109 755 - 755 2018.1

骨肉腫に対するp53誘導性腫瘍融解ウイルス療法による免疫原性細胞死の誘導効果

出宮光二, 田澤大, 田澤大, 望月雄介, 小松原将, 長谷井嬢, 中田英二, 国定俊之, 浦田泰生, 藤原俊義, 尾崎敏文

日本整形外科学会雑誌 92 ( 8 ) 2018

軟部肉腫に対するp53発現腫瘍融解アデノウイルスによるアポトーシス抑制遺伝子発現の制御を介した放射線感受性増感作用の検討

小松原将, 出宮光二, 望月雄介, 長谷井嬢, 吉田晶, 中田英二, 国定俊之, 浦田泰生, 田澤大, 藤原俊義, 尾崎敏文

日本整形外科学会雑誌 92 ( 8 ) 2018

大腸癌におけるAZIN1RNA編集の意義

重安邦俊, 重安邦俊, GOEL A., 藤原俊義

肝臓 59 ( Supplement 2 ) 2018

Bevacizumab+mFOLFOX6療法が有効であった肝内胆管癌の一例

母里淑子, 永坂岳司, 楳田祐三, 重安邦俊, 吉田一博, 岸本浩行, 香川俊輔, 藤原俊義

日本臨床腫瘍学会学術集会(CD-ROM) 16th 2018

大腸癌における新規oncogenic small nucleolar RNA(oncSNOR)の探求

吉田一博, 重安邦俊, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 安井和也, 香川俊輔, 白川靖博, 八木孝仁, GOEL Ajay, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 29th 2018

消化管外瘻を伴う炎症性腸疾患に対する腹腔鏡下手術の安全性

戸嶋俊明, 近藤善太, 小松泰浩, 三村直毅, 重安邦俊, 矢野修也, 母里淑子, 寺石文則, 岸本浩行, 香川俊輔, 藤原俊義

日本大腸肛門病学会雑誌(Web) 71 ( 9 ) 2018

StageIV大腸癌の原発巣切除後に長期予後が期待できる症例とは

寺石文則, 戸嶋俊明, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 岸本浩行, 尾崎和秀, 藤原俊義

日本大腸肛門病学会雑誌(Web) 71 ( 9 ) 2018

回腸人工肛門狭窄のリスク因子の抽出と予防

重安邦俊, 母里淑子, 戸嶋俊明, 矢野修也, 近藤喜太, 岸本浩行, 寺石文則, 藤原俊義

日本大腸肛門病学会雑誌(Web) 71 ( 9 ) 2018

鉄キレート剤の幹細胞性制御による新規癌治療法の確立

大原利章, 大原利章, 桂佑貴, 野間和広, 鳴坂徹, 二宮卓之, 友野靖子, 田澤大, 香川俊輔, 白川靖博, 松川昭博, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 29th 2018

食道癌におけるがん細胞及びがん関連線維芽細胞に対するDual-targeting Photoimmunotherapy

佐藤浩明, 野間和宏, 鳴坂徹, 河本慧, 大原利章, 田澤大, 白川靖博, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 29th 2018

A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study)

Shunsuke Kagawa, Atsushi Muraoka, Takeshi Kambara, Hiroshi Nakayama, Ryosuke Hamano, Norimitsu Tanaka, Kazuhiro Noma, Kohji Tanakaya, Hiroyuki Kishimoto, Kunitoshi Shigeyasu, Shinji Kuroda, Satoru Kikuchi, Kazuya Kuwada, Masahiko Nishizaki, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER CHEMOTHERAPY AND PHARMACOLOGY 81 ( 2 ) 387 - 392 2018

Language：English Publisher：SPRINGER

Trastuzumab when combined with fluoropyrimidine and cisplatin was proven to improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) in the ToGA study. The safety and efficacy of trastuzumab in combination with docetaxel and S-1 have not yet been evaluated.This study was a multicenter, phase II study. Patients with chemotherapy-na < ve HER2-positive advanced or metastatic GC were eligible. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 and 6 mg/kg in subsequent cycles. Docetaxel was administered intravenously at 40 mg/m(2) on day 1 of each cycle. S-1 was administered at a dosage based on body surface area for 14 days in a 3-weekly cycle. The primary endpoint was progression-free survival (PFS).A total of 23 patients were enrolled. Median PFS was 6.7 months (95% CI 4.1-10.1). The response rate (RR) was 39.1%. Median overall survival (OS) and time to treatment failure (TTF) were 17.5 and 4.4 months, respectively. Major grade 3-4 adverse events were neutropenia (39.1%), leukopenia (30.4%), and febrile neutropenia (8.7%).Trastuzumab in combination with docetaxel and S-1 showed effective antitumor activity and manageable toxicities as first-line treatment for patients with HER2-positive GC.

DOI： 10.1007/s00280-017-3505-4

Visualized Evaluation of Blood Flow to the Gastric Conduit and Complications in Esophageal Reconstruction. International journal

Kazuhiro Noma, Yasuhiro Shirakawa, Nobuhiko Kanaya, Tsuyoshi Okada, Naoaki Maeda, Takayuki Ninomiya, Shunsuke Tanabe, Kazufumi Sakurama, Toshiyoshi Fujiwara

Journal of the American College of Surgeons 226 ( 3 ) 241 - 251 2018

Language：English

BACKGROUND: Evaluation of the blood supply to gastric conduits is critically important to avoid complications after esophagectomy. We began visual evaluation of blood flow using indocyanine green (ICG) fluorescent imaging in July 2015, to reduce reconstructive complications. In this study, we aimed to statistically verify the efficacy of blood flow evaluation using our simplified ICG method. STUDY DESIGN: A total of 285 consecutive patients who underwent esophagectomy and gastric conduit reconstruction were reviewed and divided into 2 groups: before and after introduction of ICG evaluation. The entire cohort and 68 patient pairs after propensity score matching (PS-M) were evaluated for clinical outcomes and the effect of visualized evaluation on reducing the risk of complication. RESULTS: The leakage rate in the ICG group was significantly lower than in the non-ICG group for each severity grade, both in the entire cohort (285 subjects) and after PS-M; the rates of other major complications, including recurrent laryngeal nerve palsy and pneumonia, were not different. The duration of postoperative ICU stay was approximately 1 day shorter in the ICG group than in the non-ICG group in the entire cohort, and approximately 2 days shorter after PS-M. Visualized evaluation of blood flow with ICG methods significantly reduced the rate of anastomotic complications of all Clavien-Dindo (CD) grades. Odds ratios for ICG evaluation decreased with CD grade (0.3419 for CD ≥ 1; 0.241 for CD ≥ 2; and 0.2153 for CD ≥ 3). CONCLUSIONS: Objective evaluation of blood supply to the reconstructed conduit using ICG fluorescent imaging reduces the risk and degree of anastomotic complication.

DOI： 10.1016/j.jamcollsurg.2017.11.007

食道胃接合部癌切除後の観音開き法を用いた腹腔鏡下経裂孔食道残胃吻合

西崎正彦, 野間和広, 田邊俊介, 二宮卓之, 前田直見, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 72nd 2018

鞘と層の微細解剖に留意した左反回神経周囲リンパ節郭清手技定型化の工夫

白川靖博, 前田直見, 田辺俊介, 野間和広, 楳田祐三, 藤原俊義

日本胸部外科学会定期学術集会(Web) 71st 2018

食道癌外科診療における周術期チーム連携PERiO:Perioperative management center

白川靖博, 小川俊博, 前田直見, 二宮卓之, 田辺俊介, 野間和広, 楳田祐三, 西崎正彦, 香川俊輔, 藤原俊義

日本消化器外科学会雑誌(Web) 51 ( Supplement1 ) 2018

胸部食道癌手術における血流評価を元に行う安全な胃管・空腸再建法

野間和広, 白川靖博, 西脇紀之, 松田達雄, 前田直見, 田辺俊介, 藤原俊義

日本胸部外科学会定期学術集会(Web) 71st 2018

気道瘻を有する局所進行食道癌の開胸手術における合併症予防の工夫

田辺俊輔, 白川靖博, 西脇紀之, 松田達雄, 前田直見, 野間和広, 楳田祐三, 藤原俊義

日本臨床外科学会雑誌 79 2018

集学的治療を要する肺瘻合併胸部進行食道癌の一例

田辺俊介, 白川靖博, 前田直見, 野間和広, 藤原俊義

日本胸部外科学会定期学術集会(Web) 71st 2018

癌関連線維芽細胞は腫瘍浸潤リンパ球を制御することにより食道癌の予後に寄与する

加藤卓也, 加藤卓也, 野間和広, 賀島肇, 賀島肇, 桂佑貴, 桂佑貴, 前田直見, 二宮卓之, 田邊俊介, 白川靖博, 稲垣優, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 72nd 2018

食道亜全摘手術患者における術前筋肉量が術後経過に与える影響

園井みか, 伊藤真理, 足羽孝子, 前田直見, 二宮卓之, 田邊俊介, 野間和広, 白川靖博, 藤原俊義, 森松博史

日本食道学会学術集会抄録集(CD-ROM) 72nd 2018

食道癌患者に対する腫瘍融解ウイルスの内視鏡的投与の実際-感染対策の取り組み-

矢野朋美, 采女典子, 森隆弘, 笠原由美子, 田辺俊介, 黒田新士, 野間和広, 田澤大, 香川俊輔, 白川靖博, 藤原俊義

日本消化器内視鏡技師学会プログラム・講演抄録 81st 2018

Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB. International journal

Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Kosuke Nakatani, Masashi Tachibana, Nobuyuki Kato, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

Molecular therapy oncolytics 7 76 - 85 2017.12

Language：English

Telomerase-specific replication-competent adenoviruses (Ads), i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver). We reported that inhibition of nuclear factor-κB (NF-κB) leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα) expression cassette (TRAD-DNIκBα). Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

DOI： 10.1016/j.omto.2017.10.003

Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB. International journal

Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Kosuke Nakatani, Masashi Tachibana, Nobuyuki Kato, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

Molecular therapy oncolytics 7 76 - 85 2017.12

Language：English

Telomerase-specific replication-competent adenoviruses (Ads), i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver). We reported that inhibition of nuclear factor-κB (NF-κB) leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα) expression cassette (TRAD-DNIκBα). Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

DOI： 10.1016/j.omto.2017.10.003

Iron depletion is a novel therapeutic strategy to target cancer stem cells. International journal

Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

Oncotarget 8 ( 58 ) 98405 - 98416 2017.11

Language：English

Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

DOI： 10.18632/oncotarget.21846

The characteristics and outcomes of small bowel adenocarcinoma: a multicentre retrospective observational study

Hiroyuki Sakae, Hiromitsu Kanzaki, Junichiro Nasu, Yutaka Akimoto, Kazuhiro Matsueda, Masao Yoshioka, Masahiro Nakagawa, Shinichiro Hori, Masafumi Inoue, Tomoki Inaba, Atsushi Imagawa, Masahiro Takatani, Ryuta Takenaka, Seiyu Suzuki, Toshiyoshi Fujiwara, Hiroyuki Okada

BRITISH JOURNAL OF CANCER 117 ( 11 ) 1607 - 1613 2017.11

Language：English Publisher：NATURE PUBLISHING GROUP

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1-2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA.
Methods: We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013.
Results: The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3-4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months.
Conclusions: Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.

DOI： 10.1038/bjc.2017.338

Novel therapeutic strategy for human epidermal growth factor receptor 2-positive gastric cancer

Nobuhiko Kanaya, Shinji Kuroda, Tetsushi Kubota, Toshiaki Morihiro, Satoru Kikuchi, Masahiko Nishizaki, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 44 ( 10 ) 883 - 885 2017.10

Language：Japanese Publishing type：Book review, literature introduction, etc. Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Trastuzumab (Tmab), a humanized monoclonal antibody that selectively targets human epidermal growth factor receptor 2 (HER2), is currently used in the clinical setting for the treatment of both breast and gastric cancer. While Tmab has shown improvements in patient prognoses, acquired resistance to this agent remains an issue. While some novel HER2-targeted agents have been approved for clinical use in breast cancer, no such agent has shown treatment efficacy for gastric malignancies with Tmab-resistance. Nanotechnology, which has progressed rapidly, has been applied to medical fields in recent years. Gold nanopartides, which are characterized by their in vivo stability and ease of surface modification, have been reported to show efficacy as the carriers of therapeutic agents, such as drugs, antibodies, peptides, and nucleic acids. In this work, we developed Tmab-conjugated gold nanopartides and demonstrate their efficacy for the treatment of HER2-positive, Tmab-resistant gastric cancer cell lines. Our findings demonstrate that Tmab-conjugated gold nanopartides have the potential to be a novel HER2-targeted therapeutic agent.

食道胃接合部癌に対する胸腔鏡下下縦隔郭清・腹腔鏡下下部食道噴門側胃切除 (特集食道胃接合部癌の手術) -- (経裂孔アプローチ)

野間和広, 白川靖博, 田辺俊介, 黒田新士, 西﨑正彦, 藤原俊義

手術 = Operation 71 ( 11 ) 1525 - 1529 2017.10

Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system

Katsuyuki Aoyama, Shinji Kuroda, Toshiaki Morihiro, Nobuhiko Kanaya, Tetsushi Kubota, Yoshihiko Kakiuchi, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

SCIENTIFIC REPORTS 7 ( 1 ) 1 - 8 2017.10

Language：English Publisher：NATURE PUBLISHING GROUP

Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40-50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.

DOI： 10.1038/s41598-017-14717-x

Living Donor Liver Transplantation for Acute Liver Failure: Comparing Guidelines on the Prediction of Liver Transplantation

Kazuhiro Yoshida, Yuzo Umeda, Akinobu Takaki, Takeshi Nagasaka, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kosei Takagi, Tetsuya Yasunaka, Hiroyuki Okada, Takahito Yagi, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 71 ( 5 ) 381 - 390 2017.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Determining the indications for and timing of liver transplantation (LT) for acute liver failure (ALF) is essential. The King's College Hospital (KCH) guidelines and Japanese guidelines are used to predict the need for LT and the outcomes in ALF. These guidelines' accuracy when applied to ALF in different regional and etiological backgrounds may differ. Here we compared the accuracy of new (2010) Japanese guidelines that use a simple scoring system with the 1996 Japanese guidelines and the KCH criteria for living donor liver transplantation (LDLT). We retrospectively analyzed 24 adult ALF patients (18 acute type, 6 sub-acute type) who underwent LDLT in 1998-2009 at our institution. We assessed the accuracies of the 3 guidelines' criteria for ALF. The overall 1-year survival rate was 87.5%. The new and previous Japanese guidelines were superior to the KCH criteria for accurately predicting LT for acute-type ALF (72% vs. 17%). The new Japanese guidelines could identify 13 acute-type ALF patients for LT, based on the timing of encephalopathy onset. Using the previous Japanese guidelines, although the same 13 acute-type ALF patients (72%) had indications for LT, only 4 patients were indicated at the 1st step, and it took an additional 5 days to decide the indication at the 2nd step in the other 9 cases. Our findings showed that the new Japanese guidelines can predict the indications for LT and provide a reliable alternative to the previous Japanese and KCH guidelines.

Preoperative Controlling Nutritional Status (CONUT) Score for Assessment of Prognosis Following Hepatectomy for Hepatocellular Carcinoma

Kosei Takagi, Takahito Yagi, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Hiroyuki Araki, Toshiyoshi Fujiwara

WORLD JOURNAL OF SURGERY 41 ( 9 ) 2353 - 2360 2017.9

Language：English Publisher：SPRINGER

Immune-nutritional status has been recently reported as a prognostic factor in hepatocellular carcinoma (HCC). The controlling nutritional status (CONUT) score has been established as a useful tool to evaluate immune-nutritional status. This study aimed to investigate the efficacy of the CONUT score as a prognostic factor in patients undergoing hepatectomy for HCC.
A total of 295 patients who underwent curative hepatectomy for HCC between January 2007 and December 2014 were retrospectively analyzed. Patients were divided into two groups according to the CONUT score. The impact of the CONUT score on clinicopathological, surgical, and long-term outcomes was evaluated. Subsequently, the impact of prognostic factors, including the CONUT score, associated with outcomes was assessed using multivariate analyses.
Of 295 patients, 118 (40%) belonged to the high CONUT group (CONUT score 3). The high CONUT group had a significantly lower 5-year recurrence-free survival rate than the low CONUT group (27.9 vs. 41.4%, p = 0.011) and a significantly lower 5-year overall survival rate (61.9 vs. 74.9%, p = 0.006). In multivariate analyses of prognostic factors, the CONUT score was an independent predictor of recurrence-free survival (hazard ratio = 1.64, p = 0.006) and overall survival (hazard ratio = 2.50, p = 0.001).
The CONUT score is a valuable preoperative predictor of survival in patients undergoing hepatectomy for HCC.

DOI： 10.1007/s00268-017-3985-8

IS POOR OUTCOME OF LIVING DONOR LIVER TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS THE NATURE OF THE DISEASE ITSELF OR INSUFFICIENT IMMUNOSUPPRESSION?

Takahito Yagi, Daisuke Nobuoka, Yuzo Umeda, Ryuichi Yoshida, Takashi Kuise, Kosei Takagi, Kenjiro Kumano, Toshiyoshi Fujiwara

TRANSPLANT INTERNATIONAL 30 288 - 289 2017.9

SURGICAL OUTCOMES OF LIVING DONOR LIVER SURGERY: TECHNICAL KNACK FOR ZERO MORBIDITY

Takashi Kuise, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Kenjiro Kumano, Takeshi Koujima, Kosei Takagi, Toshiyoshi Fujiwara, Takahito Yagi

TRANSPLANT INTERNATIONAL 30 128 - 129 2017.9

PREDICTION OF SALVAGE LIVER TRANSPLANTATION FOR HCC RECURRENCE: WHEN AND WHICH PATIENT SHOULD WE DECIDE TRANSPLANT?

Yuzo Umeda, Takahito Yagi, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kenjiro Kumano, Takeshi Koujima, Kosei Takagi, Takeshi Nagasaka, Toshiyoshi Fujiwara

TRANSPLANT INTERNATIONAL 30 180 - 180 2017.9

ANALYSIS OF PROGNOSTIC FACTORS OF PEDIATRIC LIVING DONOR LIVER TRANSPLANTATION: A SINGLE CENTER EXPERIENCE OF MORTALITY ZERO TRANSPLANTATION FOR CHOLESTATIC DISEASE

Takahito Yagi, Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kenjiro Kumano, Mari Yoshida, Toshiyoshi Fujiwara

TRANSPLANT INTERNATIONAL 30 158 - 159 2017.9

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction

Yasuaki Yamakawa, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

CANCER SCIENCE 108 ( 9 ) 1870 - 1880 2017.9

Language：English Publisher：WILEY

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation.

DOI： 10.1111/cas.13316

SNORA21 - An Oncogenic Small Nucleolar RNA, with a Prognostic Biomarker Potential in Human Colorectal Cancer

Kazuhiro Yoshida, Shusuke Toden, Wenhao Weng, Kunitoshi Shigeyasu, Jinsei Miyoshi, Jacob Turner, Takeshi Nagasaka, Yanlei Ma, Tetsuji Takayama, Toshiyoshi Fujiwara, Ajay Goel

EBIOMEDICINE 22 68 - 77 2017.8

Language：English Publisher：ELSEVIER SCIENCE BV

Background: Emerging evidence indicates that small nucleolar RNAs (snoRNAs) play a central role in oncogenesis. Herein, we systematically evaluated expression profiles of snoRNAs in colorectal cancer (CRC) and investigated their clinical and functional role in this malignancy.
Methods: We compared expression levels of snoRNAs between cancer and normal tissues using publicly available datasets and identified the most differentially expressed and commonly upregulated snoRNAs in CRC. These results were examined in 489 colorectal tissues to assess their clinical significance, followed by a series of in vitro and in vivo experiments to evaluate the functional role of candidate snoRNAs.
Results: Usingmultiple RNA profiling datasets, we identified consistent overexpression of SNORA21 in CRC. In the clinical validation cohorts, the expression level of SNORA21was upregulated in colorectal adenomas and cancers. Furthermore, elevated SNORA21 emerged as an independent factor for predicting poor survival. Both in vitro and in vivo experiments revealed that CRISPR/Cas9-mediated inhibition of SNORA21 expression resulted in decreased cell proliferation and invasion through modulation of multiple cancer related pathways.
Conclusions: Wesystematically identified SNORA21 as a key oncogenic snoRNA in CRC, which plays an important role in cancer progression, and might serve as an important prognostic biomarker in CRC. (C) 2017 The Authors. Published by Elsevier B.V.

DOI： 10.1016/j.ebiom.2017.07.009

Training system for laparoscopy-assisted distal gastrectomy

Shinji Kuroda, Satoru Kikuchi, Naoto Hori, Shuichi Sakamoto, Tetsuya Kagawa, Megumi Watanabe, Tetsushi Kubota, Kazuya Kuwada, Michihiro Ishida, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

SURGERY TODAY 47 ( 7 ) 802 - 809 2017.7

Language：English Publisher：SPRINGER

Purpose Laparoscopy-assisted distal gastrectomy (LADG) is likely to become a standard procedure for gastric cancer, which highlights the importance of establishing a training system in which even inexperienced surgeons can perform this procedure safely. This study assesses our training system for LADG based on short-term surgical outcomes.
Methods We evaluated retrospectively the short-term outcomes of 100 consecutive LADGs with curative D1/D1+ lymph node dissection. Our training system was assessed based on the learning curve of trainees, and factors related to achieving good-quality operations were analyzed statistically.
Results Overall, postoperative complications developed in 10 patients (10%), and included one case of anastomotic leakage (1%) and one case of pancreatic fistula (1%). The learning curve of the trainees plateaued after 10 operator cases in terms of operation time. The importance of the trainer's position was also confirmed by the result that the operation time was significantly longer when trainees with <= 10 operator cases performed LADG with a trainer as scopist vs. a trainer as the first assistant. Univariate and multivariate analyses revealed that > 10 operator cases were the most important factor for achieving good-quality operations.
Conclusion These results show that our current LADG procedure and training system are appropriate and effective.

DOI： 10.1007/s00595-016-1439-9

Circular RNA ciRS-7-A Promising Prognostic Biomarker and a Potential Therapeutic Target in Colorectal Cancer

Wenhao Weng, Qing Wei, Shusuke Toden, Kazuhiro Yoshida, Takeshi Nagasaka, Toshiyoshi Fujiwara, Sanjun Cai, Huanlong Qin, Yanlei Ma, Ajay Goel

CLINICAL CANCER RESEARCH 23 ( 14 ) 3918 - 3928 2017.7

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Colorectal cancer is one of themost common malignancies worldwide. Recently, a novel circular RNA, ciRS-7, was proposed to be a potential miR-7 sponge. As miR-7, a putative tumor-suppressor, regulates the expression of several important drivers of colorectal cancer, we analyzed the clinical significance of ciRS-7 in colorectal cancer patients.
Experimental Design: Initially, we evaluated the expression levels of ciRS-7 in a training cohort comprising of 153 primary colorectal cancer tissues and 44 matched normal mucosae. We subsequently confirmed its clinical relevance in an independent validation cohort (n = 165), and evaluated the effect of ciRS-7 on miR-7, and its target genes EGFR and RAF1. Functional analyses were performed in cell lines and an animal model to support clinical findings.
Results: Our data revealed that ciRS-7 was significantly upregulated in colorectal cancer tissues compared with matched normal mucosae (P = 0.0018), and its overexpression was associated with poor patient survival (P = 0.0224 and 0.0061 in the training and validation cohorts, respectively). Multivariate survival analysis revealed that ciRS-7 emerged as an independent risk factor for overall survival (P = 0.0656 and 0.0324 in the training and validation cohorts, respectively). Overexpression of ciRS-7 in HCT116 and HT29 cells led to the blocking of miR-7 and resulted in a more aggressive oncogenic phenotype, and ciRS-7 overexpression permitted the inhibition of miR-7 and subsequent activation of EGFR and RAF1 oncogenes.
Conclusions: CiRS-7 is a promising prognostic biomarker in colorectal cancer patients and may serve as a therapeutic target for reducing EGFR-RAF1 activity in colorectal cancer patients. (C) 2017 AACR.

DOI： 10.1158/1078-0432.CCR-16-2541

Gene expression profiles in BRAF V600E mutant colorectal cancer and association with SFRP2 methylation status

Kazuya Yasui, Takeshi Nagasaka, Toshiaki Toshima, Takashi Kawai, Kunitoshi Shigeyasu, Yoshiko Mori, Junko Haraga, Keiichiro Nakamura, Yuzo Umeda, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Novel evidence for AZIN1 RNA editing-mediated oncogenic role in colorectal cancer

Kunitoshi Shigeyasu, Shusuke Toden, Yoshinaga Okugawa, Jinsei Miyoshi, Takeshi Nagasaka, Toshiyoshi Fujiwara, Leilei Chen, Ajay Goel

CANCER RESEARCH 77 2017.7

Tumorigenesis of murine iPS cell is prevented by iron depletion with downregulation of stemness markers

Yuki Katsura, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Takayuki Ninomiya, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Cancer-associated fibroblasts contribute to tumor immunosuppression by regulating tumor-infiltrating lymphocytes

Takuya Kato, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Takayuki Ninomiya, Toshiaki Ohara, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Cancer associated fibroblasts promote tumor metastasis coexisting with cancer cells in blood circulation

Hajime Kashima, Kazuhiro Noma, Hiroaki Sato, Yuki Katsura, Takuya Kato, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Novel theranostic strategy against scirrhous gastric cancer; combination of chemotherapy and fluorescence oncolytic adenovirus

Wataru Ishikawa, Satoru Kikuchi, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Fluorescence-guided spatiotemporal dynamics of epithelial-mesenchymal transition under inflammatory microenvironment during colorectal cancer progression

Takeshi Ieda, Hiroshi Tazawa, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Takeshi Imamura, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Clinicopathological significance of endometrial cancer with MSH2 deficiency

Junko Haraga, Takeshi Nagasaka, Keiichirou Nakamura, Tomoko Haruma, Takeshi Nishida, Akihiro Nyuya, Kazuya Yasui, Hisashi Masuyama, Toshiyoshi Fujiwara, Yuji Hiramatsu

CANCER RESEARCH 77 2017.7

Hyperthermia at the single-cell level for disseminated cancer disease with immuno-magnetic nanoparticles

Tetsuya Kagawa, Hiroyuki Kishimoto, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Takeshi Nagasaka, Satoshi Nohara, Ichiro Kato, Adarsh Sandhu, Hiromichi Aono, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Primary pancreatic-type acinar cell carcinoma of the jejunum with tumor thrombus extending into the mesenteric venous system: a case report and literature review

Kosei Takagi, Takahito Yagi, Takehiro Tanaka, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Toshiyoshi Fujiwara

BMC SURGERY 17 ( 1 ) 237 - 243 2017.6

Language：English Publisher：BIOMED CENTRAL LTD

Background: Although ectopic pancreatic tissue is common in the upper gastrointestinal tract, the incidence of ectopic pancreatic tissue in the jejunum is low, and malignant transformation in ectopic pancreatic tissue is rare. Furthermore, pancreatic-type acinar cell carcinoma (ACC) developing in the jejunum and ACC accompanied by tumor thrombus are extremely rare.
Case presentation: A 78-year-old-woman presented with melena. Abdominal computed tomography images and endoscopic examination revealed a submucosal jejunal mass with tumor thrombus extending into a jejunal vein. The patient underwent a curative resection combined with a partial jejunectomy and partial pancreatectomy. Histopathological examination of the resected tissue showed tumor cells with a homogeneous acinar architecture identical to pancreatic-type ACC and tumor thrombus. Postoperatively, she was followed for 10 months and had no recurrence.
Conclusion: We present an extremely rare case of pancreatic-type ACC in the jejunum with extensive tumor thrombus invading into the mesenteric venous system. This type of cancer has not been reported previously but should be considered in the differential diagnosis of a jejunal mass.

DOI： 10.1186/s12893-017-0273-3

Management of early gastric cancer that meet the indication for radical lymph node dissection following endoscopic resection: a retrospective cohort analysis

Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Tetsuya Kagawa, Hiromitsu Kanzaki, Yoshiro Kawahara, Shunsuke Kagawa, Takehiro Tanaka, Hiroyuki Okada, Toshiyoshi Fujiwara

BMC SURGERY 17 ( 1 ) 687 - 694 2017.6

Language：English Publisher：BIOMED CENTRAL LTD

Background: Endoscopic resection (ER) has been widely accepted as the standard treatment for early gastric cancer (EGC). However, in patients considered to have undergone non-curative ER due to their potential risk of lymph node metastasis (LNM), additional gastrectomy is recommended. The aim of the present study was to identify EGC patients after non-curative ER at high risk of LNM.
Methods: A total of 150 patients who had undergone ER for EGC were diagnosed as non-curative ER due to their potential risk of LNM. Clinicopathological data and clinical outcomes were examined retrospectively.
Results: Additional gastrectomy with lymph node dissection was performed in 73 patients, and the remaining 77 patients were followed-up without additional gastrectomy. In patients who underwent additional gastrectomy, 8 patients had local residual tumor, and 8 patients had LNM, which were limited in the peritumoral nodes. Only lymphatic invasion (p = 0.012) was a statistically significant factor for LNM. The 5-year overall survival and recurrence-free survival were not significantly different between patients with and without additional gastrectomy.
Conclusion: Additional gastrectomy with lymph node dissection is recommended for patients who were diagnosed as non-curative ER with lymphatic invasion, and minimizing the extent of lymph node dissection may be allowed for these patients.

DOI： 10.1186/s12893-017-0268-0

Radiographic sarcopenia predicts postoperative infectious complications in patients undergoing pancreaticoduodenectomy

Kosei Takagi, Ryuichi Yoshida, Takahito Yagi, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Toshiyoshi Fujiwara

BMC SURGERY 17 ( 1 ) 453 - 466 2017.5

Language：English Publisher：BIOMED CENTRAL LTD

Background: Recently, skeletal muscle depletion (sarcopenia) has been reported to influence postoperative outcomes after certain procedures. This study investigated the impact of sarcopenia on postoperative outcomes following pancreaticoduodenectomy (PD).
Methods: We performed a retrospective study of consecutive patients (n = 219) who underwent PD at our institution between January 2007 and May 2013. Sarcopenia was evaluated using preoperative computed tomography. We evaluated postoperative outcomes and the influence of sarcopenia on short-term outcomes, especially infectious complications. Subsequently, multivariate analysis was used to assess the impact of prognostic factors (including sarcopenia) on postoperative infections.
Results: The mortality, major complication, and infectious complication rates for all patients were 1.4%, 16.4%, and 47.0%, respectively. Fifty-five patients met the criteria for sarcopenia. Sarcopenia was significantly associated with a higher incidence of in-hospital mortality (P = 0.004) and infectious complications (P < 0.001). In multivariate analyses, sarcopenia (odds ratio = 3.43; P < 0.001), preoperative biliary drainage (odds ratio = 2.20; P = 0.014), blood loss (odds ratio = 1.92; P = 0.048), and soft pancreatic texture (odds ratio = 3.71; P < 0.001) were independent predictors of postoperative infections.
Conclusions: Sarcopenia is an independent preoperative predictor of infectious complications after PD. Clinical assessment combined with sarcopenia may be helpful for understanding the risk of postoperative outcomes and determining perioperative management strategies.

DOI： 10.1186/s12893-017-0261-7

Nonexposure laparoscopic and endoscopic cooperative surgery (closed laparoscopic and endoscopic cooperative surgery) for gastric submucosal tumor

Satoru Kikuchi, Masahiko Nishizaki, Shinji Kuroda, Shunsuke Tanabe, Kazuhiro Noma, Shunsuke Kagawa, Yasuhiro Shirakawa, Hiroshi Kato, Hiroyuki Okada, Toshiyoshi Fujiwara

GASTRIC CANCER 20 ( 3 ) 553 - 557 2017.5

Language：English Publisher：SPRINGER

Laparoscopic and endoscopic cooperative surgery (LECS) is increasingly applied for gastric submucosal tumors (SMTs) such as gastrointestinal stromal tumors. However, the conventional LECS procedure has the potential risk that gastric contents and even tumor cells could spread into the abdominal cavity because the gastric wall has to be opened during the resection. To avoid this problem, we have developed a modified LECS procedure named "closed LECS." Ten patients underwent closed LECS for the resection of gastric SMTs. Closed LECS consists of the following steps: endoscopic submucosal layer dissection around the tumor, laparoscopic marking of a resection line on the serosal surface along submucosal dissection line, seromuscular suturing with the marked lesion inverted into the inside of the stomach, endoscopic circumferential seromuscular dissection, and peroral retrieval. In three of the initial five cases, the closed LECS procedure was not completed as planned because of the tumor size and endoscopic inappropriate seromuscular dissection. After modification of the procedure, the entire procedure was successful in all five cases. The mean resected tumor diameter was 24.1 +/- 7.6 mm. The mean operation time was 253 +/- 45 min. One patient experienced an intra-abdominal abscess potentially related to delayed perforation as a postoperative complication. The closed LECS procedure for gastric SMTs can theoretically be applied without contamination and tumor cell dissemination into the abdominal cavity.

DOI： 10.1007/s10120-016-0641-1

Outcome of Radiation Monotherapy for High-risk Patients with Stage I Esophageal Cancer

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Shunsuke Tanabe, Shinji Kuroda, Shunsuke Kagawa, Kuniaki Katsui, Norihisa Katayama, Susumu Kanazawa, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 71 ( 2 ) 127 - 133 2017.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Currently, chemoradiation is the most widely used nonsurgical treatment for esophageal cancer. However, some patients, particularly the very elderly or those with severe vital organ dysfunction, face difficulty with the chemotherapy component. We therefore examined the outcome of radiation therapy (RT) alone for patients with esophageal cancer at our facility. Between January 2005 and December 2014, 84 patients underwent RT at our hospital, and 78 of these patients received concomitant chemotherapy. The remaining 6 patients underwent RT alone; these patients were considered to be high-risk and to have no lymph node metastasis (stage I). Five of them received irradiation up to a curative dose: 4 showed a complete response (CR) and 1 showed a partial response (PR). Of the patients exhibiting CR, 3 are currently living recurrence-free, whereas 1 patient underwent endoscopic submucosal dissection (ESD) as salvage therapy for local recurrence, with no subsequent recurrence. High-risk stage I esophageal cancer patients can be treated radically with RT alone under certain conditions. In the future, to broaden the indications for RT monotherapy to include some degree of advanced cancers, a novel concurrent therapy should be identified.

Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers

Takayuki Iwamoto, Toyomasa Katagiri, Naoki Niikura, Yuichiro Miyoshi, Mariko Kochi, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Masako Omori, Yutaka Tokuda, Toshiyoshi Fujiwara, Hiroyoshi Doihara, Balazs Gyorffy, Junji Matsuoka

ONCOTARGET 8 ( 16 ) 26122 - 26128 2017.4

Language：English Publisher：IMPACT JOURNALS LLC

Background: The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers.
Results: Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P < 0.001). PostKi67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P < 0.001 and 0.041, respectively).
Materials and Methods: Core needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre-and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed.
Conclusions: IHC based post-Ki67 levels may have distinct predictive power compared with the naive IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

DOI： 10.18632/oncotarget.15385

High-metastatic triple-negative breast-cancer variants selected in vivo become chemoresistant in vitro

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 4 ) 285 - 287 2017.4

IDENTIFICATION OF A CIRCULATING MIRNA DIAGNOSTIC SIGNATURE IN PANCREATIC DUCTAL ADENOCARCINOMA

Kazuhiro Yoshida, Shusuke Toden, Haiyong Han, Susan Tsai, Murtaza Muhammed, Scott Celinski, Carlos Becerra, Takeshi Nagasaka, Toshiyoshi Fujiwara, Douglas B. Evans, Danniel V. Hoff, Ajay Goel

GASTROENTEROLOGY 152 ( 5 ) S273 - S273 2017.4

Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

JOURNAL OF CELLULAR BIOCHEMISTRY 118 ( 3 ) 559 - 569 2017.3

Language：English Publisher：WILEY-BLACKWELL

We previously developed and characterized a highly invasive and metastatic triple-negative breast cancer (TNBC) variant by serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Eventually, a highly invasive and metastatic variant of human TNBC was isolated after lymph node metastases was harvested and orthotopically re-implanted into the mammary gland of nude mice for two cycles. The variant thereby isolated is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present report, we observed that high-metastatic MDA-MB-231H-RFP cells produced significantly larger subcutaneous tumors compared with parental MDA-MB-231 cells in nude mice. Extensive lymphatic trafficking by high-metastatic MDA-MB-231 cells was also observed. High-metastatic MDA-MB-231 developed larger recurrent tumors 2 weeks after tumor resection compared with tumors that were not resected in orthotopic models. Surgical resection of the MDA-MB-231 high-metastatic variant primary tumor in orthotopic models also resulted in rapid and enhanced lymphatic trafficking of residual cancer cells and extensive lymph node and lung metastasis that did not occur in the non-surgical mice. These results suggest that surgical resection of high metastatic TNBC can greatly increase the malignancy of residual cancer. J. Cell. Biochem. 118: 559-569, 2017. (c) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.25735

Early Chimerism After Liver Transplantation Reflects the Clinical Course of Recurrent Hepatitis C

Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Takahiro Oto, Motoo Araki, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

ANNALS OF TRANSPLANTATION 22 156 - 165 2017.3

Language：English Publisher：INT SCIENTIFIC LITERATURE, INC

Background: Human leukocyte antigen (HLA) mismatch is a characteristic feature of post-orthotopic liver transplantation (OLT) hepatitis C. To investigate the importance of donor HLA-restricted immune cells in post-OLT hepatitis C recurrence, we analyzed the frequency of donor chimerism and the clinical course of post-OLT hepatitis C.
Material/Methods: We analyzed peripheral blood chimerism in 11 HCV-reinfected patients with post-HLA mismatched OLT. Patients were divided into 2 groups: the OLT chronic hepatitis C (CHC) group (n=8), exhibiting active hepatitis C recurrence; and the OLT-persistently normal ALT (PNALT) group (n=3), without active hepatitis. Chimerism was analyzed by flow cytometry using donor-specific anti-HLA antibodies in peripheral blood mononuclear cells from 1-100 days after OLT. Kidney (n=7) and lung (n=7) transplant recipients were also analyzed for comparison. As immune cells from the donor liver might contribute to post-OLT chimerism, the characteristics of perfusates from donor livers (n=10) were analyzed and defined.
Results: Donor-derived cells were frequently observed in liver and lung transplant recipients. The frequency of donor-derived cells from the B cell subset was significantly higher in peripheral blood from OLT-CHC group than in that of the OLT-PNALT group. B cells, however, were not the predominant subset in the perfusates, indicating that inflow of donor-derived cells alone did not cause the chimerism.
Conclusions: Chimerism of B cells is frequent in liver transplant patients with early recurrence of hepatitis C. We propose that monitoring of early chimerism could facilitate early detection of chronic hepatitis C recurrence, although we need more cases to investigate.

DOI： 10.12659/AOT.900494

A Novel "Shrug Technique" for Totally Implantable Venous Access Devices via the External Jugular Vein: A Consecutive Series of 254 Patients

Tetsuya Kagawa, Satoshi Ueyama, Tatsunori Kobayashi, Hiroki Okabayashi, Shinji Kuroda, Toshiyoshi Fujiwara

JOURNAL OF SURGICAL ONCOLOGY 115 ( 3 ) 291 - 295 2017.3

Language：English Publisher：WILEY

Background: The external jugular vein (EJV) approach for totally implantable venous access devices (TIVADs) is safe. However, the success rate is unsatisfactory because of the difficulty in catheterization due to the acute angle between the EJV and the subclavian vein (SCV). A novel "shrug technique" to overcome this difficulty was developed, and its efficacy was assessed in a consecutive case series.
Methods: TIVAD placement was performed via the EJV cut-down approach. "Shrug technique," a simple way to straighten the EJV-SVC angle by shrugging the patient's shoulder, was applied to facilitate the passage of the guidewire and sheath-introducer when there was acute angulation between the EJV and SCV.
Results: A total of 254 patients underwent TIVAD implantation by the EJV cut-down approach. The " shrug technique" was applied in 51 cases (20%), and catheterization was successful in all cases. Thus, TIVAD implantation was successfully completed in all 254 cases (100%) in a single operative setting. The median operating time was 38 [IQR 30-45] min. Eleven complications (4%) were observed, but none of them were EJV-specific.
Conclusion: The " shrug technique" is simple but very useful to achieve a higher success rate and safer insertion of TIVADs from the EJV. (C) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/jso.24504

A Novel "Shrug Technique" for Totally Implantable Venous Access Devices via the External Jugular Vein: A Consecutive Series of 254 Patients

Tetsuya Kagawa, Satoshi Ueyama, Tatsunori Kobayashi, Hiroki Okabayashi, Shinji Kuroda, Toshiyoshi Fujiwara

JOURNAL OF SURGICAL ONCOLOGY 115 ( 3 ) 291 - 295 2017.3

Language：English Publisher：WILEY

Background: The external jugular vein (EJV) approach for totally implantable venous access devices (TIVADs) is safe. However, the success rate is unsatisfactory because of the difficulty in catheterization due to the acute angle between the EJV and the subclavian vein (SCV). A novel "shrug technique" to overcome this difficulty was developed, and its efficacy was assessed in a consecutive case series.
Methods: TIVAD placement was performed via the EJV cut-down approach. "Shrug technique," a simple way to straighten the EJV-SVC angle by shrugging the patient's shoulder, was applied to facilitate the passage of the guidewire and sheath-introducer when there was acute angulation between the EJV and SCV.
Results: A total of 254 patients underwent TIVAD implantation by the EJV cut-down approach. The " shrug technique" was applied in 51 cases (20%), and catheterization was successful in all cases. Thus, TIVAD implantation was successfully completed in all 254 cases (100%) in a single operative setting. The median operating time was 38 [IQR 30-45] min. Eleven complications (4%) were observed, but none of them were EJV-specific.
Conclusion: The " shrug technique" is simple but very useful to achieve a higher success rate and safer insertion of TIVADs from the EJV. (C) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/jso.24504

OBP-401-GFP telomerase-dependent adenovirus illuminates and kills high-metastatic more effectively than low-metastatic triple-negative breast cancer in vitro

S. Yano, K. Takehara, H. Kishimoto, H. Tazawa, Y. Urata, S. Kagawa, M. Bouvet, T. Fujiwara, R. M. Hoffman

CANCER GENE THERAPY 24 ( 2 ) 45 - 47 2017.2

Language：English Publisher：NATURE PUBLISHING GROUP

We previously described the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. The isolated variant is highly invasive in the mammary gland and Metastasized to lymph nodes in 10 of 12 mice compared with 2 of 12 of the parental cell line. OBP-401 is a telomerase-dependent cancer-specific, green fluorescent protein (GFP)-expressing adenovirus. OBP-401 was used to infect parental MDA-MB-231P cells and high-metastatic MDA-MB-231H and MDA-MB-231HLN isolated from a lymph node metastasis and MDA-MB-231HLM isolated from a lung metastasis. Time-course imaging showed that OBP-401 labeled MDA-MB-231HP, MDA-MB-231HLN, and MDA-MB-231HLM cells more brightly than MDA-MB-231 parental cells. OBP-401 killed MDA-MB-231H, MDA-MB-231HLN, and MDA-MB-231HLM cells more efficiently than MDA-MB-231P parental cells. These results indicate that OBP-401 could infect, label and then kill high-metastatic MDA-MB-231 more efficiently than low-metastatic MDA-MB-231.

DOI： 10.1038/cgt.2016.67

Comparison of in vitro invasiveness of high- and low-metastatic triple-negative human breast cancer visualized by color-coded imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 2 ) 96 - 98 2017.2

Syndrome of Inappropriate Antidiuretic Hormone Secretion Following Liver Transplantation

Kosei Takagi, Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Nobuyuki Watanabe, Takashi Kuise, Tomokazu Fuji, Hiroyuki Araki, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 71 ( 1 ) 85 - 89 2017.2

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an extremely rare cause of hyponatremia post-liver transplantation. A 15-year-old Japanese girl with recurrent cholangitis after Kasai surgery for biliary atresia underwent successful living donor liver transplantation. Peritonitis due to gastrointestinal perforation occurred. Hyponatremia gradually developed but improved after hypertonic sodium treatment. One month later, severe hyponatremia rapidly recurred. We considered the hyponatremia's cause as SIADH. We suspected that tacrolimus was the disease's cause, so we used cyclosporine instead, plus hypertonic sodium plus water intake restriction, which improved the hyponatremia. Symptomatic hyponatremia manifested by SIADH is a rare, serious complication post-liver transplantation.

Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Michael Bouvet, Robert M. Hoffman

ANTICANCER RESEARCH 37 ( 1 ) 57 - 60 2017.1

Language：English Publisher：INT INST ANTICANCER RESEARCH

Background: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. Materials and Methods: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. Results: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDAMB- 231 tumors were resected. Conclusion: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC.

DOI： 10.21873/anticanres.11288

Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer

Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Masashi Tachibana, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

MOLECULAR CANCER THERAPEUTICS 16 ( 1 ) 251 - 259 2017.1

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter- driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing shorthairpin RNA against Dicer (shDicer; TRAD-shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity. (C) 2016 AACR.

DOI： 10.1158/1535-7163.MCT-16-0383

Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study

Nobuaki Suzuki, Shoichi Hazama, Haruo Iguchi, Kazuhiro Uesugi, Hiroaki Tanaka, Kosei Hirakawa, Atsushi Aruga, Takashi Hatori, Hidenobu Ishizaki, Yuzo Umeda, Toshiyoshi Fujiwara, Tetsuya Ikemoto, Mitsuo Shimada, Kazuhiko Yoshimatsu, Ryoichi Shimizu, Hiroto Hayashi, Koichiro Sakata, Hiroko Takenouchi, Hiroto Matsui, Yoshitaro Shindo, Michihisa Iida, Yasunobu Koki, Hideki Arima, Hiroyuki Furukawa, Tomio Ueno, Shigefumi Yoshino, Yusuke Nakamura, Masaaki Oka, Hiroaki Nagano

CANCER SCIENCE 108 ( 1 ) 73 - 80 2017.1

Language：English Publisher：WILEY-BLACKWELL

We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naive PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

DOI： 10.1111/cas.13113

Sarcopenia predicts postoperative infection in patients undergoing hepato-biliary-pancreatic surgery

Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Toshiyoshi Fujiwara

International Journal of Surgery Open 6 12 - 18 2017

Language：English Publisher：Elsevier Ltd

Background Operative mortality and morbidity rates after hepato-biliary-pancreatic (BILI) surgery remain high. This study evaluated clinical characteristics and surgical outcomes of patients who underwent BILI surgery and investigated predictors of outcomes by focusing on sarcopenia. Materials and methods A prospective observational study was performed for consecutive patients who underwent BILI surgery at our institution between June 2013 and May 2014. Sarcopenia was evaluated using computed tomography. Surgical outcomes and the influence of sarcopenia on outcomes were evaluated. Subsequently, the impact of prognostic factors, including sarcopenia, associated with postoperative infections was assessed using multivariate analyses. Results Total mortality, major complications, and infectious disease rates for all 157 patients were 0%, 9.6%, and 21.7%, respectively. Thirty-eight patients met the criteria for sarcopenia. The sarcopenic group had a significantly higher incidence of infectious complications compared to the non-sarcopenic group (36.8% vs. 17.2%
P = 0.015). During multivariate analyses of prognostic factors, sarcopenia (hazard ratio = 2.44
P = 0.043) and diabetes mellitus (hazard ratio = 3.07
P = 0.01) were detected as independent predictors of postoperative infections. Conclusions Sarcopenia is an independent preoperative predictor of infection after BILI surgery. Earlier diagnosis and therapeutic intervention for patients with sarcopenia could be useful in the development of comprehensive approaches for perioperative care.

DOI： 10.1016/j.ijso.2016.12.002

Primary pancreatic-type acinar cell carcinoma of the jejunum with tumor thrombus extending into the mesenteric venous system: a case report and literature review

Takagi K, Yagi T, Tanaka T, Umeda Y, Yoshida R, Nobuoka D, Kuise T, Fujiwara T

BMC Surg 17 ( 75 ) doi: 10.1186/s12893-017-0273-3 2017

Management of early gastric cancer that meet the indication for radical lymph node dissection following endoscopic resection: a retrospective cohort analysis

Kikuchi S, Kuroda S, Nishizaki M, Kagawa T, Kanzaki H, Kawahara Y, Kagawa S, Tanaka T, Okada H, Fujiwara T

BMC Surg 17 ( 1 ) doi: 10.1186/s12893-017-0268-0 2017

GFP labeling kinetics of triple-negative human breast cancer by a killer-reporter adenovirus in 3D Gelfoam® histoculture

Yano S, Takehara K, Miwa S, Kishimoto H, Tazawa H, Urata Y, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

In Vitro Cell Dev Biol Anim 53 ( 6 ) 479 - 482 2017

胃癌術後再発病変に対する複数回の放射線療法が奏功し長期生存が得られた1例

堀直人, 香川俊輔, 菊地覚次, 黒田新士, 渡邉めぐみ, 坂本修一, 香川哲也, 桒田和也, 久保田哲史, 岸本浩行, 西﨑正彦, 片山敬久, 藤原俊義

癌と化学療法 44 ( 2 ) 165 - 167 2017

[Multiple Salvage Radiotherapies for Metachronous Lymph Node Metastasis from Gastric Cancer Contributed to Long-Term Management of Disease].

Naoto Hori, Shunsuke Kagawa, Satoru Kikuchi, Shinji Kuroda, Megumi Watanabe, Shuichi Sakamoto, Tetsuya Kagawa, Kazuya Kuwada, Tetsushi Kubota, Hiroyuki Kishimoto, Masahiko Nishizaki, Norihisa Katayama, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 2 ) 165 - 167 2017

Language：Japanese

A 70-year-old man who underwent gastrectomy for Stage III C gastric cancer developed lymph node(LN)metastasis posterior to the pancreatic head 3 years after the radical surgery.He was first treated with radiotherapy(RT)followed by chemotherapy.The irradiated tumor regressed completely.However, the cancer relapsed in a single para-aortic LN and he was treated with RT to the lesion followed by chemotherapy.Although it completely regressed, later, lung metastasis was observed.The lung lesions were well suppressed by switching to docetaxel; however, the cancer relapsed again in a mediastinal LN, and it was not responsive to docetaxel.The growing mediastinal lesion was irradiated again, which resulted in stable disease.The patient has been treated for 4 years and 7 months with all lesions being well-managed, and chemotherapy is being continued.Recurrent gastric cancer after surgery tends to present as multiple lesions; therefore, the principle therapy is systemic chemotherapy and RT is unlikely to be suitable.However, especially in cases of a solitary lesion that is chemo-resistant, RT could be an optimal option and contribute to long-term survival even in patients with recurrent gastric cancer.

GFP labeling kinetics of triple-negative human breast cancer by a killer-reporter adenovirus in 3D Gelfoam? histoculture

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert, M. Hoffman

In Vitro Cellular and Developmental Biology - Plant, In Vitro Cellular and Developmental Biology - Animal 1 - 4 2017

Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 16 ( 5 ) 406 - 414 2017

Language：English Publisher：TAYLOR & FRANCIS INC

We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cell-cycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G(2) phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression.

DOI： 10.1080/15384101.2016.1220461

Thoracoscopic esophagectomy was effective in a case of lower esophageal stenosis due to recurrence of achalasia after myotomy 40 years previously

Katsura Yuki, Shirakawa Yasuhiro, Tanabe Shunsuke, Maeda Naomi, Noma Kazuhiro, Fujiwara Toshiyoshi

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 129 ( 1 ) 41 - 44 2017

Language：Japanese Publisher：Okayama Medical Association

When planning surgery for achalasia, it is important to plan for adequate myotomy and prevention of reflux. However, achalasia may recur if the procedure was inadequate or in patients with a long-term course. The present case is a 68-year-old woman who underwent myotomy of the lower esophageal sphincter 40 years ago, but recently reported difficulty in swallowing. Dilatation of the thoracic esophagus and stenosis of the abdominal esophagus were identified by examination, and the patient was diagnosed with recurrence of achalasia. After percutaneous endoscopic gastrostomy was performed to recover nutritional status, thoracoscopic esophagectomy was carried out. The patient's post-operative course was uneventful and oral intake was enabled. At the time of writing, there has been no re-recurrence. There is no standard therapy for post-operative recurrence of achalasia. We believe that thoracoscopic esophagectomy for the recurrence of achalasia is a safe and minimally invasive alternative to conventional surgery.

DOI： 10.4044/joma.129.41

Other Link： http://search.jamas.or.jp/link/ui/2017219750

食道胃接合部癌に対する下部食道噴門側胃切除術-腹臥位胸腔鏡・腹腔鏡アプローチによる完全鏡視下手術-

野間和広, 白川靖博, 田辺俊介, 黒田新士, 西﨑正彦, 藤原俊義

手術 71 ( 5 ) 767 - 772 2017

Radiographic sarcopenia predicts postoperative infectious complications in patients undergoing pancreaticoduodenectomy

Takagi K, Yoshida R, Yagi T, Umeda Y, Nobuoka D, Kuise T, Fujiwara T

BMC Surg 17 ( 64 ) DOI: 10.1186/s12893-017-0261-7 2017

A case of long-term survival after surgical resection for solitary adrenal recurrence of esophageal squamous carcinoma

Kanaya N, Noma K, Okada T, Maeda N, Tanabe S, Sakurama K, Shirakawa Y, Fujiwara T

Surg Case Rep 3 ( 61 ) doi: 10.1186/s40792-017-0337-8 2017

Comparison of outcomes between symptomatic and asymptomatic patients with colorectal cancer: a propensity score-matched analysis of surgical invasiveness, medical costs and oncological outcomes. International journal

Ryo Inada, Takeshi Nagasaka, Ayako Watanabe, Tomohiko Yagi, Yoshiko Mori, Yoshitaka Kondo, Hiroyuki Kishimoto, Yuzo Umeda, Toshiyoshi Fujiwara

BMJ open gastroenterology 4 ( 1 ) doi: 10.1136/bmjgast-2017-000146 2017

Language：English

BACKGROUND AND AIMS: Whether asymptomatic patients with colorectal cancer (CRC) who are treated in hospitals show better outcomes than symptomatic patients with CRC still remains unknown. The aim of this study was to evaluate differences in clinical benefits following treatment in asymptomatic and symptomatic patients with CRC. METHODS: This study was a retrospective cohort analysis with data obtained from records. A cohort of 145 asymptomatic and 123 symptomatic patients who underwent CRC surgery between January 2009 and December 2011 was enrolled. To reduce bias in comparing outcomes, propensity score (PS) analysis was used for matching of patients in the symptomatic and asymptomatic groups based on clinicopathological factors. Surgical invasiveness, medical costs and oncological outcomes were examined by unadjusted and PS-matched analysis. RESULTS: Tumours in the symptomatic group were more often diagnosed in advanced stages compared with tumours in the asymptomatic group. Therefore, fewer symptomatic group patients underwent minimally invasive surgery. Short-term outcomes, including amount of blood loss, duration of postoperative hospital stay and perioperative medical costs, were significantly better in the asymptomatic group. Although overall survival was significantly better in the asymptomatic group, there was no significant difference between the groups when the patients were adjusted on the basis of PS. CONCLUSIONS: Though this study was limited by the retrospective nature and small sample size, favourable outcomes in asymptomatic patients were due to the higher proportion of patients in this group who were diagnosed with CRC in earlier stages, due to participation in CRC screening programmes.

DOI： 10.1136/bmjgast-2017-000146

Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer

Tazawa H, Kuroda S, Hasei J, Kagawa S, Fujiwara T

Int J Mol Sci 18 ( 7 ) doi:10.3390/ijms18071479 2017

Eradication of melanoma in vitro and in vivo via targeting with a Killer-Red-containing telomerase-dependent adenovirus

Kiyoto Takehara, Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Nobuhiro Narii, Hiroyuki Mizuguchi, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert, M. Hoffman

Cell Cycle 1 - 7 2017

A novel intestinal rotation method for digestive reconstruction after combined pancreaticoduodenectomy and extended right hemicolectomy: A case report and surgical technique

Kosei Takagi, Takahito Yagi, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kenjiro Kumano, Takeshi Kojima, Takuro Fushimi, Toshiyoshi Fujiwara

International Journal of Surgery Case Reports 39 51 - 55 2017

Language：English Publisher：Elsevier Ltd

Introduction Pancreaticoduodenectomy (PD) combined with extended right hemicolectomy (RH) is a challenging procedure for locally advanced malignancies. However, information concerning the reconstruction method of the digestive system is limited. Here, we present a case and surgical technique of a novel intestinal rotation method for digestive reconstruction after PD combined with RH. Presentation of case A 62-year-old man with locally advanced pancreatic cancer received conversion surgery combined with PD and RH after preoperative chemotherapy. With respect to the reconstruction of the digestive system, the entire intestinal mesentery was rotated 180° forward counterclockwise around the axis of the superior mesenteric artery, and then the reconstruction, according to Child's method, was performed. The patient recovered without problems in gastroenterological functions after the operation. Discussion With respect to the reconstruction of the digestive system in patients undergoing combined PD and RH, practitioners should pay close attention to twisting of the intestinal mesentery when bringing up the proximal jejunum for pancreatojejunostomy and hepatojejunostomy and the distal ileum for ileocolic anastomosis. This intestinal rotation method enables a smooth and uneventful reconstruction of the digestive system. Conclusion This is the first detailed description of an intestinal rotation method for digestive reconstruction after combined PD and extended RH. The intestinal rotation method can be an alternative and helpful technical option for digestive reconstruction in patients with combined PD and RH.

DOI： 10.1016/j.ijscr.2017.07.063

Role of zoledronic acid in oncolytic virotherapy

Yasuaki Yamakawa, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancer Science, Japanese Journal of Cancer Research, Gann, The Japanese Journal of Cancer Research 149 - 160 2017

Visualized Evaluation of Blood Flow to the Gastric Conduit and Complications in Esophageal Reconstruction. International journal

Kazuhiro Noma, Yasuhiro Shirakawa, Nobuhiko Kanaya, Tsuyoshi Okada, Naoaki Maeda, Takayuki Ninomiya, Shunsuke Tanabe, Kazufumi Sakurama, Toshiyoshi Fujiwara

Journal of the American College of Surgeons 226 ( 3 ) 858 - 867 2017

Language：English

BACKGROUND: Evaluation of the blood supply to gastric conduits is critically important to avoid complications after esophagectomy. We began visual evaluation of blood flow using indocyanine green (ICG) fluorescent imaging in July 2015, to reduce reconstructive complications. In this study, we aimed to statistically verify the efficacy of blood flow evaluation using our simplified ICG method. STUDY DESIGN: A total of 285 consecutive patients who underwent esophagectomy and gastric conduit reconstruction were reviewed and divided into 2 groups: before and after introduction of ICG evaluation. The entire cohort and 68 patient pairs after propensity score matching (PS-M) were evaluated for clinical outcomes and the effect of visualized evaluation on reducing the risk of complication. RESULTS: The leakage rate in the ICG group was significantly lower than in the non-ICG group for each severity grade, both in the entire cohort (285 subjects) and after PS-M; the rates of other major complications, including recurrent laryngeal nerve palsy and pneumonia, were not different. The duration of postoperative ICU stay was approximately 1 day shorter in the ICG group than in the non-ICG group in the entire cohort, and approximately 2 days shorter after PS-M. Visualized evaluation of blood flow with ICG methods significantly reduced the rate of anastomotic complications of all Clavien-Dindo (CD) grades. Odds ratios for ICG evaluation decreased with CD grade (0.3419 for CD ≥ 1; 0.241 for CD ≥ 2; and 0.2153 for CD ≥ 3). CONCLUSIONS: Objective evaluation of blood supply to the reconstructed conduit using ICG fluorescent imaging reduces the risk and degree of anastomotic complication.

DOI： 10.1016/j.jamcollsurg.2017.11.007

Preoperative Controlling Nutritional Status (CONUT) Score for Assessment of Prognosis Following Hepatectomy for Hepatocellular Carcinoma

Kosei Takagi, Takahito Yagi, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Hiroyuki Araki, Toshiyoshi Fujiwara

World Journal of Surgery, Bulletin de la Societe internationale de chirurgie 1 - 8 2017

Therapeutic Cell-Cycle-Decoy Efficacy of a Telomerase-Dependent Adenovirus in an Orthotopic Model of Chemotherapy-Resistant Human Stomach Carcinomatosis Peritonitis Visualized With FUCCI Imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert, M. Hoffman

Journal of Cellular Biochemistry, Journal of Supramolecular and Cellular Biochemistry, Journal of supramolecular structure 476 - 479 2017

Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer

Shindo Y, Hazama S, Suzuki N, Iguchi H, Uesugi K, Tanaka H, Aruga A, Hatori T, Ishizaki H, Umeda Y, Fujiwara T, Ikemoto T, Shimada M, Yoshimatsu K, Takenouchi H, Matsui H, Kanekiyo S, Iida M, Koki Y, Arima H, Furukawa H, Ueno T, Yoshino S, Fujita T, Kawakami Y, Nakamura Y, Oka M, Nagano H

J Exp Clin Cancer Res 36 ( 1 ) doi: 10.1186/s13046-017-0509-1 2017

OBP-401-GFP telomerase-dependent adenovirus illuminates and kills high-metastatic more effectively than low-metastatic triple-negative breast cancer in vitro.

Yano S, Takehara K, Kishimoto H, Tazawa H, Urata Y, Kagawa S, Bouvet M, Fujiwara T, Hoffman R.M

Cancer Gene Therapy 20 ( 2 ) 45 - 47 2017

Living donor liver transplantation for acute liver failure

Kazuhiro Yoshida, Yuzo Umeda, Akinobu Takaki, Takeshi Nagasaka, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kosei Takagi, Tetsuya Yasunaka, Hiroyuki Okada, Takahito Yagi, Toshiyoshi Fujiwara

Acta Medica Okayama, Acta. Medica Okayama, Acta medicinae Okayama, Acta medica Okayama 71 ( 5 ) 381 - 390 2017

癌関連線維芽細胞は食道癌のリンパ節転移を促進するか~臨床検体の解析と同所移植モデルを用いた検証~

賀島肇, 野間和広, 佐藤浩明, 桂佑貴, 加藤卓也, 大原利章, 田澤大, 白川靖博, 藤原俊義

日本がん転移学会学術集会・総会プログラム抄録集 26th 2017

遅発性に肝転移・骨盤内リンパ節転移をきたした直腸神経内分泌腫瘍の1例

重安邦俊, 杭瀬崇, 母里淑子, 河合毅, 矢野修也, 戸嶋俊明, 浅野博昭, 近藤喜太, 佃和憲, 永坂岳司, 八木孝仁, 藤原俊義

日本大腸肛門病学会雑誌(Web) 70 2017

癌関連線維芽細胞はIL-6を分泌しリンパ球の遊走を制御することで腫瘍免疫抑制を誘導する

加藤卓也, 野間和広, 賀島肇, 桂佑貴, 佐藤浩明, 二宮卓之, 大原利章, 藤原俊義

日本がん転移学会学術集会・総会プログラム抄録集 26th 2017

HER2陽性胃癌に対する新たな治療戦略

金谷信彦, 黒田新士, 久保田哲史, 森廣俊昭, 菊地覚次, 西崎正彦, 田澤大, 香川俊輔, 藤原俊義

癌と化学療法 44 ( 10 ) 883 - 885 2017

Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system

Aoyama K, Kuroda S, Morihiro T, Kanaya N, Kubota T, Kakiuchi Y, Kikuchi S, Nishizaki M, Kagawa S, Tazawa H, Fujiwara T

Sci Rep 7 ( 14177 ) doi: 10.1038/s41598-017-14717-x 2017

The characteristics and outcomes of small bowel adenocarcinoma: a multicentre retrospective observational study

Sakae H, Kanzaki H, Nasu J, Akimoto Y, Matsueda K, Yoshioka M, Nakagawa M, Hori S, Inoue M, Inaba T, Imagawa A, Takatani M, Takenaka R, Suzuki S, Fujiwara T, Okada H

Br J Cancer 117 ( 11 ) 1607 - 1613 2017

Eradication of melanoma in vitro and in vivo via targeting with a Killer-Red-containing telomerase-dependent adenovirus

Kiyoto Takehara, Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Nobuhiro Narii, Hiroyuki Mizuguchi, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 16 ( 16 ) 1502 - 1508 2017

Language：English Publisher：TAYLOR & FRANCIS INC

Melanoma is a highly recalcitrant cancer and transformative therapy is necessary for the cure of this disease. We recently developed a telomerase-dependent adenovirus containing the fluorescent protein Killer-Red. In the present report, we first determined the efficacy of Killer-Red adenovirus combined with laser irradiation on human melanoma cell lines in vitro. Cell viability of human melanoma cells was reduced in a dose-dependent and irradiation-time-dependent manner. We used an intradermal xenografted melanoma model in nude mice to determine efficacy of the Killer-Red adenovirus. Intratumoral injection of Killer-Red adenovirus, combined with laser irradiation, eradicated the melanoma indicating the potential of a new paradigm of cancer therapy.

DOI： 10.1080/15384101.2016.1249548

ウイルス療法とは

藤原俊義

がん免疫療法 1 ( 1 ) 51 - 52 2017

食道がんに対する放射線併用ウイルス療法の臨床研究

藤原俊義, 田澤大, 田邊俊介, 香川俊輔, 白川靖博

日本臨床 75 ( 5 ) 746 - 751 2017

噴門側胃切除術後再建：手縫い腹腔鏡下体腔内手縫い「観音開き法」食道残胃吻合

西﨑正彦, 黒田新士, 菊地覚次, 垣内慶彦, 松村年久, 渡邉めぐみ, 香川俊輔, 藤原俊義

臨床外科 72 ( 4 ) 412 - 415 2017

「外科臨床研究の基礎と実践」によせて

藤原俊義

日本外科学会雑誌 118 ( 4 ) 466 - 466 2017

胃癌におけるサルコペニアの意義

桒田和也, 黒田新士, 藤原俊義

消化器外科 40 ( 7 ) 1042 - 1048 2017

HOZOT細胞を用いた腫瘍融解ウイルス製剤のDDS

田澤大, 大西哲平, 香川俊輔, 中村修治, 藤原俊義

BIO INDUSTRY 34 ( 4 ) 16 - 23 2017

ウイルス療法第3回がんウイルス療法の臨床試験

藤原俊義

がん免疫療法 1 ( 2 ) 118 - 120 2017

生体肝移植ドナー手術後区域グラフト採取術

八木孝仁, 楳田祐三, 吉田龍一, 信岡大輔, 藤原俊義

手術 71 ( 10 ) 1383 - 1388 2017

がんウイルス療法

藤原俊義

腫瘍内科 20 ( 2 ) 171 - 176 2017

ウイルス療法第2回がん治療に用いられるウイルス

藤原俊義

がん免疫療法 1 ( 2 ) 115 - 117 2017

臨床応用されるp53研究現状と今後の課題進化するp53遺伝子を用いたがんウイルス療法

藤原俊義

実験医学 35 ( 14 ) 2364 - 2365 2017

超高齢者の進行食道癌に対し積極的に集学的治療を行い長期無再発生存中の1例

松三雄騎, 白川靖博, 田邊俊介, 河本慧, 前田直見, 二宮卓之, 野間和広, 西崎正彦, 香川俊輔, 藤原俊義

癌と化学療法 44 ( 12 ) 1784 - 1786 2017

Successful management of unresectable small bowel lymphoma with laparoscopy-assisted surgical exclusion of the affected intestine

Kagawa T, Kobayashi T, Ueyama S, Okabayashi H, Ogino T, Fujiwara T

Asian J Endosc Surg 10 ( 4 ) 454 - 458 2017

観音開き法を用いた噴門機能温存

西﨑正彦, 黒田新士, 菊地覚次, 垣内慶彦, 香川俊輔, 藤原俊義

手術 71 ( 1 ) 21 - 25 2017

臨床研究中核病院の現状と今後の展望

藤原俊義

岡山医学会雑誌 129 ( 3 ) 179 - 184 2017

有茎空腸による食道再建

白川靖博, 河本慧, 松三雄騎, 前田直見, 二宮卓之, 田辺俊介, 櫻間教文, 野間和広, 藤原俊義

臨床雑誌外科 79 ( 4 ) 355 - 359 2017

胸部食道癌に対する頸部リンパ節郭清術

白川靖博, 野間和広, 田辺俊介, 藤原俊義

消化器外科 40 ( 5 ) 508 - 515 2017

Oncolytic virotherapy for osteosarcoma

Pharm stage 16 ( 12 ) 54 - 59 2017

腹腔鏡内視鏡合同手術外科医の立場から

西﨑正彦, 岡田裕之, 藤原俊義

日本消化器病学会雑誌 114 ( 2 ) 218 - 223 2017

気管気管支リンパ節郭清における左気管支動脈温存のための安全なアプローチ

白川靖博, 前田直見, 二宮卓之, 田辺俊介, 野間和広, 藤原俊義

手術 71 ( 4 ) 367 - 374 2017

食道癌手術後に反回神経麻痺を呈した患者における肺炎のリスク因子について

池田朋大, 野澤康明, 伊藤真理, 足羽孝子, 二宮卓之, 前田直見, 田邊俊介, 野間和広, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 71st 2017

腎癌の多発膵転移・単発肺転移・下大静脈腫瘍栓に対して膵全摘を含めた一期的切除を施行し良好な術後経過を得た一例

國府島健, 信岡大輔, 八木孝仁, 楳田祐三, 吉田龍一, 杭瀬崇, 熊野健二郎, 高木弘誠, 伏見卓郎, 谷本竜太, 藤原俊義

日本膵切研究会プログラム・抄録集 44th 2017

胸腔鏡下食道癌手術における膜と層の微細解剖に基づいた上縦隔リンパ節郭清

白川靖博, 前田直見, 田辺俊介, 野間和広, 藤原俊義

日本胸部外科学会定期学術集会(Web) 70th 2017

食道鏡視下手術におけるリンパ節郭清のTipsメルクマールとV字郭清法

野間和広, 白川靖博, 前田直見, 田辺俊介, 藤原俊義

日本胸部外科学会定期学術集会(Web) 70th 2017

鏡視下食道癌手術におけるピットフォールとトラブルシューティング

河本慧, 田邊俊介, 白川靖博, 松三雄騎, 前田直見, 二宮卓之, 野間和広, 藤原俊義

日本消化器外科学会雑誌(Web) 50 ( Supplement1 ) 2017

食道がん患者の術前看護外来前と入院時の抑うつ傾向と心理的適応の変化

廣川万里子, 市川あい, 伊藤真理, 足羽孝子, 前田直見, 二宮卓之, 田邊俊介, 野間和広, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 71st 2017

食道癌患者における術前目標体重管理への取り組みが術後の食習慣習得に与える影響

園井みか, 足羽孝子, 伊藤真理, 前田直見, 二宮卓之, 田邊俊介, 野間和広, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 71st 2017

腹臥位胸腔鏡下食道切除における微細層構造を意識した安全な上縦隔郭清術

野間和広, 白川靖博, 鳴坂徹, 前田直見, 二宮卓之, 田辺俊介, 楳田祐三, 西崎正彦, 香川俊輔, 藤原俊義

日本内視鏡外科学会雑誌 22 ( 7 (CD-ROM) ) 2017

進行食道癌に対するDCF療法を用いた集学的治療

田邊俊介, 白川靖博, 河本慧, 松三雄騎, 前田直見, 二宮卓之, 野間和広, 西崎正彦, 香川俊輔, 藤原俊義

日本消化器外科学会雑誌(Web) 50 ( Supplement1 ) 2017

食道癌手術における臨床応用解剖の経験

前田直見, 白川靖博, 田辺俊介, 野間和広, 藤原俊義

日本胸部外科学会定期学術集会(Web) 70th 2017

80歳以上の超高齢者に対する安全な食道癌治療への取り組み

田辺俊介, 白川靖博, 前田直見, 野間和広, 香川俊輔, 藤原俊義

日本胸部外科学会定期学術集会(Web) 70th 2017

In Vivo Selection of Intermediately- and Highly-Malignant Variants of Triple-negative Breast Cancer in Orthotopic Nude Mouse Models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ANTICANCER RESEARCH 36 ( 12 ) 6273 - 6277 2016.12

Language：English Publisher：INT INST ANTICANCER RESEARCH

Aim: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2 (HER2), is a recalcitrant disease in need of effective therapy. We previously isolated very-highly metastatic variants of the TNBC cell line MDA-MB-231 using serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (MDA-MB-231-RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation into the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for three or seven cycles in order to isolate intermediately, or highly-metastatic variants, respectively. Results: The degree of malignancy of isolated variants of MDA-MB-231 depends on the extent of orthotopic transplantation. Serial transplantation resulted in MDA-MB-231-RFP which significantly produced larger tumors compared with the parental MDA-MB-231-RFP. Serial orthotopic implantation for three cycles resulted in intermediately-metastatic variants of MDA-MB-231-RFP. MDA-MB-231-RFP serially orthotopically transplanted seven times significantly metastasized more to lymph nodes compared with parental MDA-MB-231-RFP cells and the intermediately-metastatic variant. The highly-metastatic variant MDA-MB-231-RFP cells significantly metastasized to the lung to a greater extent compared with parental MDA-MB-231-RFP and intermediate variants of MDA-MB-231-RFP. Conclusion: These results suggest that the number of serial orthotopic transplantations of MDA-MB-231-RFP correlates positively with tumor aggressiveness, and the intermediately- and highly-metastatic variants can serve as models of metastatic progression of TNBC.

DOI： 10.21873/anticanres.11222

A successful case of deceased donor liver transplantation for a patient with intrahepatic arterioportal fistula

Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Nobuyuki Watanabe, Takashi Kuise, Kenta Sui, Akira Hirose, Makiko Tsuboi, Mitsunari Ogasawara, Shinji Iwasaki, Toshiji Saibara, Toshiyoshi Fujiwara

HEPATOLOGY RESEARCH 46 ( 13 ) 1409 - 1415 2016.12

Language：English Publisher：WILEY

Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension that is often difficult to treat with interventional radiology or surgery. Liver transplantation for IAPF is extremely rare. We report a case of bilateral diffuse IAPF with severe portal hypertension requiring deceased donor liver transplantation (DDLT). A 51-year-old woman with no past medical history was admitted to another hospital complaining of abdominal distension and marasmus. A computed tomography scan and digital subtraction angiography indicated a massive pleural effusion, ascites, and a very large IAPF. Several attempts of interventional embolization of the feeding artery failed to ameliorate arterioportal shunt flow. As ruptures of the esophageal varices became more frequent, hepatic encephalopathy worsened. After repeated, uncontrollable attacks of hepatic coma, the patient was referred to our facility for further treatment. Surgical approaches to IAPF other than liver transplantation were challenging because of diffuse collateralization; therefore, we placed the patient on the national waiting list for DDLT. Although her Model for End-Stage Liver Disease score was relatively low, she received a DDLT 2 months after the waiting period. The postoperative course was uneventful, and the patient was discharged 44 days after her transplant. Liver transplantation may be a valid treatment option for uncontrollable IAPF with severe portal hypertension.

DOI： 10.1111/hepr.12701

Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 7 ( 51 ) 85273 - 85282 2016.12

Language：English Publisher：IMPACT JOURNALS LLC

Our laboratory previously developed a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of the human MDA-MB-231 cell line in nude mice. The isolated variant was highly-invasive in the mammary gland and lymphatic channels and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present study, the tumor-selective telomerase dependent OBP-401 adenovirus was injected intratumorally (i. t.) (1 x 10(8) PFU) when the high-metastatic MDA-MB-231 primary tumor expressing red fluorescent protein (MDA-MB-231-RFP) reached approximately 500 mm3 (diameter; 10 mm). The mockinfected orthotopic primary tumor grew rapidly. After i. t. OBP-401 injection, the growth of the orthotopic tumors was arrested. Six weeks after implantation, the fluorescent area and fluorescence intensity showed no increase from the beginning of treatment. OBP-401 was then injected into high-metastatic MDA-MB-231-RFP primary orthotopic tumor growing in mice which already had developed metastasis within lymphatic ducts. All 7 of 7 control mice subsequently developed lymph node metastasis. In contrast, none of 7 mice which received OBP-401 had lymph node metastasis. Seven of 7 control mice also had gross lung metastasis. In contrast, none of the 7 mice which received OBP-401 had gross lung metastasis. Confocal laser microscopy imaging demonstrated that all control mice had diffuse lung metastases. In contrast, all 7 mice which received OBP-401 only had a few metastatic cells in the lung. OBP-401 treatment significantly extended survival of the treated mice.

DOI： 10.18632/oncotarget.13296

Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 7 ( 46 ) 75635 - 75647 2016.11

Language：English Publisher：IMPACT JOURNALS LLC

We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative highinvasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model.

DOI： 10.18632/oncotarget.12314

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Teppei Onishi, Hiroshi Tazawa, Yuuri Hashimoto, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai, Hiroyuki Mizuguchi, Hiroyuki Kishimoto, Yuzo Umeda, Yasuhiro Shirakawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Scientific Reports 6 ( 38060 ) doi: 10.1038/srep38060 2016.11

Language：English Publisher：NATURE PUBLISHING GROUP

"Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35-loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

DOI： 10.1038/srep38060

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Teppei Onishi, Hiroshi Tazawa, Yuuri Hashimoto, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai, Hiroyuki Mizuguchi, Hiroyuki Kishimoto, Yuzo Umeda, Yasuhiro Shirakawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Scientific Reports 6 2016.11

Language：English Publisher：NATURE PUBLISHING GROUP

"Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35-loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

DOI： 10.1038/srep38060

Real-time in-vivo image-guided cell-cycle perturbation to increase tumor chemosensitivity

Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Yoshihiko Kadowaki, Nobuhiro Ishido, Takahiro Okamoto, Yasuo Urata, Kiyoto Takehara, Robert M. Hoffman, Toshiyoshi Fujiwara

MOLECULAR CANCER RESEARCH 14 2016.11

Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer

Seishi Nishitani, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Shinichiro Watanabe, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF ONCOLOGY 49 ( 4 ) 1351 - 1359 2016.10

Language：English Publisher：SPANDIDOS PUBL LTD

Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.

DOI： 10.3892/ijo.2016.3640

Sarcopenia and American Society of Anesthesiologists Physical Status in the Assessment of Outcomes of Hepatocellular Carcinoma Patients Undergoing Hepatectomy

Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 70 ( 5 ) 363 - 370 2016.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Sarcopenia following liver surgery has been reported as a predictor of poor prognosis. Here we investigated predictors of outcomes in patients with hepatocellular carcinoma (HCC) and attempted to establish a new comprehensive preoperative assessment protocol. We retrospectively analyzed the cases of 254 patients who underwent curative hepatectomy for HCC with Child-Pugh classification A at our hospital between January 2007 and December 2013. Sarcopenia was evaluated by computed tomography measurement. The influence of sarcopenia on outcomes was evaluated. We used multivariate analyses to assess the impact of prognostic factors associated with outcomes, including sarcopenia. Of the 254 patients, 118 (46.5) met the criteria for sarcopenia, and 32 had an American Society of Anesthesiologists (ASA) physical status >= 3. The sarcopenic group had a significantly lower 5-year overall survival rate than the non-sarcopenic group (58.2 vs. 82.4, p=0.0002). In multivariate analyses of prognostic factors, sarcopenia was an independent predictor of poor survival (hazard ratio [HR]= 2.28, p= 0.002) and poor ASA status (HR= 3.17, p= 0.001). Sarcopenia and poor ASA status are independent preoperative predictors for poor outcomes after hepatectomy. The preoperative identification of sarcopenia and ASA status might enable the development of comprehensive approaches to assess surgical eligibility.

DOI： 10.18926/AMO/54594

A Phase II Clinical Trial of the Efficacy and Safety of Short-term (3 days) Enoxaparin for the Prevention of Venous Thromboembolism after Gastric Cancer Surgery

Shinji Kuroda, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Shiro Hinotsu, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 70 ( 5 ) 401 - 404 2016.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Although intermittent pneumatic compression (IPC) has become common as perioperative prophylaxis for venous thromboembolism (VTE) consisting of pulmonary thromboembolism (PE) and deep vein thrombosis (DVT), the prophylactic effect against VTE, especially lethal PE, is not yet satisfactory. Therefore, pharmacologic prophylaxis, such as with enoxaparin, is desirable. While the efficacy and safety of enoxaparin have been proven in several clinical trials, concern about bleeding with long-term (at least 7 days) use have potentially decreased its widespread adoption. We have launched a phase II study to evaluate the efficacy and safety of short-term (3 days) enoxaparin, in which a total of 70 gastric cancer patients undergoing gastrectomy will be recruited, and the primary endpoint is the incidence of DVT. This study could contribute to making pharmacologic prophylaxis for VTE more common.

DOI： 10.18926/AMO/54601

Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam (R)-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

PLOS ONE 11 ( 9 ) doi: 10.1371/journal.pone.0162991 2016.9

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam (R) histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam (R) grew into tumor-like structures with G(0)/G(1) cancer cells in the center and S/G(2) cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam (R) histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam (R). In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN45 cells in tumors on Gelfoam (R) to cycle from G(0)/G(1) phase to S/G(2) phase and reduced their viability. CDDP-or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam 1. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam (R) histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

DOI： 10.1371/journal.pone.0162991

Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam (R)-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

PLOS ONE 11 ( 9 ) 2016.9

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam (R) histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam (R) grew into tumor-like structures with G(0)/G(1) cancer cells in the center and S/G(2) cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam (R) histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam (R). In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN45 cells in tumors on Gelfoam (R) to cycle from G(0)/G(1) phase to S/G(2) phase and reduced their viability. CDDP-or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam 1. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam (R) histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

DOI： 10.1371/journal.pone.0162991

Double-Flap Technique as an Antireflux Procedure in Esophagogastrostomy after Proximal Gastrectomy

Shinji Kuroda, Masahiko Nishizaki, Satoru Kikuchi, Kazuhiro Noma, Shunsuke Tanabe, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 223 ( 2 ) E7 - E13 2016.8

Study about the Efficacy of Metformin to Immune Function in Cancer Patients

Mototsugu Watanabe, Hiromasa Yamamoto, Shingo Eikawa, Kazuhiko Shien, Tadahiko Shien, Junichi Soh, Katsuyuki Hotta, Jun Wada, Shiro Hinotsu, Toshiyoshi Fujiwara, Katsuyuki Kiura, Hiroyoshi Doihara, Shinichiro Miyoshi, Heiichiro Udono, Shinichi Toyooka

ACTA MEDICA OKAYAMA 70 ( 4 ) 327 - 330 2016.8

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8(+) T cells, which produce multiple cytokines.

DOI： 10.18926/AMO/54514

In Vivo Isolation of a Highly-aggressive Variant of Triple-negative Human Breast Cancer MDA-MB-231 Using Serial Orthotopic Transplantation

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ANTICANCER RESEARCH 36 ( 8 ) 3817 - 3820 2016.8

Language：English Publisher：INT INST ANTICANCER RESEARCH

Aim: We describe the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation in the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically reimplanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for two cycles and then isolated. Results: The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. Conclusion: The availability of a highly invasive variant of TNBC targeting lymph nodes will be very useful for drug discovery of TNBC, a recalcitrant cancer and for mechanistic studies of its aggressiveness.

Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms

Kazuhiro Yoshida, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Keisuke Kimura, Fumitaka Taniguchi, Tomokazu Fuji, Kunitoshi Shigeyasu, Yoshiko Mori, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 142 ( 7 ) 1557 - 1569 2016.7

Language：English Publisher：SPRINGER

Although limited understanding exists for the presence of specific genetic mutations and aberrantly methylated genes in pancreatobiliary intraductal papillary mucinous neoplasms (IPMNs), the fundamental understanding of the dynamics of methylation expansion across CpG dinucleotides in specific gene promoters during carcinogenesis remains unexplored. Expansion of DNA methylation in some gene promoter regions, such as EFEMP1, one of the fibulin family, with tumor progression has been reported in several malignancies. We hypothesized that DNA hypermethylation in EFEMP1 promoter would expand with the tumor grade of IPMN.
A sample of 65 IPMNs and 30 normal pancreatic tissues was analyzed. IPMNs were divided into the following three subsets according to pathological findings: 31 with low-grade dysplasia (low grade), 11 with high-grade dysplasia (high grade), and 23 with associated invasive carcinoma (invasive Ca). Mutations in the KRAS or GNAS genes were analyzed by Sanger sequencing, and methylation status of two discrete regions within the EFEMP1 promoter, namely region 1 and region 2, was analyzed by bisulfite sequencing and fluorescent high-sensitive assay for bisulfite DNA (Hi-SA). Expression status of EFEMP1 was investigated by immunohistochemistry (IHC).
KRAS mutations were detected in 39, 55, and 70 % of low-grade, high-grade, and invasive Ca, respectively. GNAS mutations were observed in 32, 55, and 22 % of low-grade, high-grade, and invasive Ca, respectively. The methylation of individual regions (region 1 or 2) in the EFEMP1 promoter was observed in 84, 91, and 87 % of low-grade, high-grade, and invasive Ca, respectively. However, simultaneous methylation of both regions (extensive methylation) was exclusively detected in 35 % of invasive Ca (p = 0.001) and five of eight IPMNs (63 %) with extensive methylation, whereas 20 of 57 (35.1 %) tumors of unmethylation or partial methylation of the EFEMP1 promoter region showed weak staining EFEMP1 in extracellular matrix (p = 0.422). In addition, extensive EFEMP1 methylation was particularly present in malignant tumors without GNAS mutations and associated with disease-free survival of patients with IPMNs (p < 0.0001).
Extensive methylation of the EFEMP1 gene promoter can discriminate invasive from benign IPMNs with superior accuracy owing to their stepwise accumulation of tumor progression.

DOI： 10.1007/s00432-016-2164-x

PD-L1 expression as a predictive factor for recurrence pattern and prognosis in curatively resected gastric cancer

Toshiaki Morihiro, Shinji Kuroda, Tetsushi Kubota, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

Prognostic correlation of tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs) in patients with human esophageal carcinoma

Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hajime Kashima, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

A novel live imaging system for inflammation-induced epithelial-mesenchymal transition in colorectal cancers

Takeshi Ieda, Hiroshi Tazawa, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

Iron control is a novel therapeutic target of cancer stem cells

Toshiaki Ohara, Takayuki Ninomiya, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

Functional analysis of tumor associated macrophage utilizing virus-guided fluorescent imaging of pancreatic cancer cells in the peritoneal cavity

Kazuya Kuwada, Shunsuke Kagawa, Megumi Watanabe, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Tetuya Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

Novel HER2-targeted gold nanoparticles; integration of antibody therapy and nanotechnology

Tetsushi Kubota, Shinji Kuroda, Toshiaki Morihiro, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

Correlation of FAP(fibroblast activation protein)-expressing cancer associated fibroblasts (CAFs) and tumor metastasis in esophageal carcinoma

Hajime Kashima, Kazuhiro Noma, Yuki Katsura, Takuya Kato, Ryoichi Katsube, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

Genome-wide enhancer analysis identifies PVT1 as an oncogenic enhancer of MYC

Kunitoshi Shigeyasu, Shusuke Toden, Takeshi Nagasaka, Toshiyoshi Fujiwara, C. Richard Boland, Ajay Goel

CANCER RESEARCH 76 2016.7

Virally enhanced p53 reactivation impairs KRAS-driven pancreatic cancer invasion

Takeshi Koujima, Hiroshi Tazawa, Takeshi Leda, Kazuya Kuwada, Terutaka Tanimoto, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 76 2016.7

Clinical significance of SNORA21, an H/ACA box snoRNA, as a metastasis predicting and prognostic biomarker in colorectal cancer

Kazuhiro Yoshida, Shusuke Toden, Wenhao Weng, Takeshi Nagasaka, Toshiyoshi Fujiwara, Ajay Goel

CANCER RESEARCH 76 2016.7

Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

SCIENTIFIC REPORTS 6 2016.6

Language：English Publisher：NATURE PUBLISHING GROUP

Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

DOI： 10.1038/srep28953

Surgical Outcome of Patients Undergoing Pancreaticoduodenectomy: Analysis of a 17-Year Experience at a Single Center

Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Kenta Sui, Tomokazu Fuji, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 70 ( 3 ) 197 - 203 2016.6

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

The operative mortality and morbidity of pancreaticoduodenectomy (PD) remain high. We analyzed PD patients' clinical characteristics and surgical outcomes and discuss how PD clinical outcomes could be improved. We retrospectively reviewed the cases of 400 patients who underwent a PD between January 1998 and April 2014 at Okayama University Hospital, a very-high-volume center. We identified and compared the clinical outcomes between two time periods (period 1: 1998-2006 vs. period 2: 2007-2014). The total postoperative mortality and major complication rates were 0.75 and 15.8, respectively, and the median postoperative length of stay (LOS) was 32 days. Subsequently, patients who underwent a PD during period 2 had a significantly shorter LOS than those who underwent a PD during period 1 (29 days vs. 38.5 days, p<0.001). The incidence of mortality and major complications did not differ between the two periods. In our multivariate analysis, period 1 was an independent factor associated with a long LOS (p<0.001). The improvement of the surgical procedure and perioperative care might be related to the shorter LOS in period 2 and to the consistently maintained low mortality rate after PD. The development of multimodal strategies to accelerate postoperative recovery may further improve PD's clinical outcomes.

DOI： 10.18926/AMO/54419

Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion

Satoru Kikuchi, Shunsuke Kagawa, Toshiaki Ohara, Tetsushi Kubota, Kazuya Kuwada, Tetsuya Kagawa, Shinji Kuroda, Yasuhiro Shirakawa, Masahiko Nishizaki, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 70 ( 3 ) 213 - 216 2016.6

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called "dysplasia-like atypia" (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence.

DOI： 10.18926/AMO/54421

Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

SCIENTIFIC REPORTS 6 ( 28953 ) doi: 10.1038/srep28953 2016.6

Language：English Publisher：NATURE PUBLISHING GROUP

Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

DOI： 10.1038/srep28953

Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus

Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

JOURNAL OF ORTHOPAEDIC RESEARCH 34 ( 5 ) 836 - 844 2016.5

Language：English Publisher：WILEY-BLACKWELL

In a previous study, we developed fluorescence-guided surgery (FGS) for osteosarcoma using an orthotopic model with 143B human osteosarcoma cells expressing red fluorescent protein (RFP) implanted into the intramedullary cavity of the tibia in nude mice. The FGS-treated mice had a significantly higher disease-free survival (DFS) rate than the bright-light surgery (BLS). However, although FGS significantly reduced the recurrence of the primary tumor, it did not reduce lung metastasis. In the present study, we utilized the OBP-401 telomerase-dependent killer-reporter adenovirus, carrying green fluorescent protein (GFP), to label human osteosarcoma in situ in orthotopic mouse models. OBP-401-illuminated human osteosarcoma cell lines, 143B and MNNG/HOS cells in vitro and in vivo. OBP-401 tumor illumination enabled effective FGS of the 143B-derived orthotopic mouse model of human osteosarcoma model as well as FGS eradication of residual cancer cells after BLS. OBP-401-assisted FGS significantly inhibited local recurrence and lung metastasis after surgery, thereby prolonging DFS and overall survival (OS), achieving a very important improvement of therapeutic outcomes over our previously reported FGS study. These therapeutic benefits of FGS were demonstrated using a clinically-viable methodology of direct labeling of human osteosarcoma in situ with the OBP-401 killer-reporter adenovirus in contrast with previous reports, which used genetically engineered labeled cells or antibody-based fluorescent labels for FGS. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:836-844, 2016.

DOI： 10.1002/jor.23073

Diminished Gastric Resection Preserves Better Quality of Life in Patients with Early Gastric Cancer

Hiroshi Isozaki, Sasau Matsumoto, Shigeki Murakami, Takehiro Takama, Tatuo Sho, Kiyohiro Ishihara, Kunihiko Sakai, Masanori Takeda, Koji Nakada, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 70 ( 2 ) 119 - 130 2016.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Using the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, we compared the surgical outcomes and the quality of life (QOL) between patients undergoing limited gastrectomies and those undergoing conventional gastrectomies. In Oomoto Hospital between January 2004 and December 2013, a total of 124 patients who met the eligibility criteria were enrolled. Using the main outcome measures of PGSAS-45, we compared 4 types of limited gastrectomy procedures (1/2 distal gastrectomy [1/2DG] in 21 patients; pylorus-preserving gastrectomy [PPG] in 15 patients; segmental gastrectomy [SG] in 26 patients; and local resection [LR] in 13 patients) with conventional gastrectomy (total gastrectomy [TG] in 24 patients and 2/3 or more distal gastrectomy [WDG] in 25 patients). The TG group showed the worst QOL in almost all items of the main outcome measures. The 1/2DG, PPG, and SG groups showed better QOL than the WDG group in many of the main outcome measures, including the body weight ratio, total symptom score, ingested amount of food per meal, and the dissatisfaction for daily life subscale. The LR group showed a better intake of food than the 1/2DG, PPG, and SG groups. The body weight ratio of the LR group was better than that of the SG group. Diminished gastric resection preserved better QOL in patients with early gastric cancer.

DOI： 10.18926/AMO/54191

Adenoviral targeting of malignant melanoma for fluorescence-guided surgery prevents recurrence in orthotopic nude-mouse models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 7 ( 14 ) 18558 - 18572 2016.4

Language：English Publisher：IMPACT JOURNALS LLC

Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing.

DOI： 10.18632/oncotarget.6670

A PARTIAL REVISION OF SURGICAL GLOSSARY (WEB EDITION)

Fujiwara Toshiyoshi

Journal of Japan Surgical Society 117 ( 2 ) 91 - 91 2016.3

Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Shirakawa, Hiroshi Tazawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

MOLECULAR CANCER THERAPEUTICS 15 ( 3 ) 402 - 411 2016.3

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. Wehypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)-mediated PIT induced selective cell death of HER2-ECD-transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700-mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer. (C) 2016 AACR.

DOI： 10.1158/1535-7163.MCT-15-0644

Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Yukihiko Hiroshima, Takashi Murakami, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

PLOS ONE 11 ( 2 ) doi: 10.1371/journal.pone.0148760. 2016.2

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.

DOI： 10.1371/journal.pone.0148760

Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Yukihiko Hiroshima, Takashi Murakami, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

PLOS ONE 11 ( 2 ) 2016.2

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.

DOI： 10.1371/journal.pone.0148760

Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Kiyoto Takehara, Hiroshi Tazawa, Naohiro Okada, Yuuri Hashimoto, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Yasuhiro Shirakawa, Nobuhiro Narii, Hiroyuki Mizuguchi, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

MOLECULAR CANCER THERAPEUTICS 15 ( 1 ) 199 - 208 2016.1

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Photodynamic therapy (PDT) is a minimally invasive antitumor therapy that eradicates tumor cells through a photosensitizer-mediated cytotoxic effect upon light irradiation. However, systemic administration of photosensitizer often makes it difficult to avoid a photosensitive adverse effect. The red fluorescent protein KillerRed generates reactive oxygen species (ROS) upon green light irradiation. Here, we show the therapeutic potential of a novel tumor-specific replicating photodynamic viral agent (TelomeKiller) constructed using the human telomerase reverse transcriptase (hTERT) promoter. We investigated the light-induced antitumor effect of TelomeKiller in several types of human cancer cell lines. Relative cell viability was investigated using an XTT assay. The in vivo antitumor effect was assessed using subcutaneous xenografted tumor and lymph node metastasis models. KillerRed accumulation resulted in ROS generation and apoptosis in light-irradiated cancer cells. Intratumoral injection of TelomeKiller efficiently delivered the KillerRed protein throughout the tumors and exhibited a long-lasting antitumor effect with repeated administration and light irradiation in mice. Moreover, intratumorally injected TelomeKiller could spread into the regional lymph node area and eliminate micrometastasis with limited-field laser irradiation. Our results suggest that KillerRed has great potential as a novel photosensitizer if delivered with a tumor-specific virus-mediated delivery system. TelomeKiller-based PDT is a promising antitumor strategy to efficiently eradicate tumor cells. (C) 2015 AACR.

DOI： 10.1158/1535-7163.MCT-15-0344

Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy

Masahiro Sugihara, Hiroshi Sadamori, Masahiro Nishibori, Yasuharu Sato, Hiroshi Tazawa, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Kyotaro Ohno, Takeshi Nagasaka, Tadashi Yoshino, Hideo Kohka Takahashi, Takahito Yagi, Toshiyoshi Fujiwara

AMERICAN JOURNAL OF SURGERY 211 ( 1 ) 179 - 188 2016.1

Language：English Publisher：EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC

BACKGROUND: The purpose of this study is to determine the effects of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) on ischemia/reperfusion injury (IRI) and the mode of liver regeneration.
METHODS: Rats underwent 70% hepatectomy with IRI caused by clamping the hepatoduodenal ligament for 20 minutes, followed by the administration of anti-HMGB1 mAb immediately before declamping the hepatoduodenal ligament. Five animals were used for each time point. We then evaluated IRI, regeneration parameters and the status of HMGB1 in remnant livers.
RESULTS: The anti-HMGB1 mAb significantly ameliorated the degree of IRI in the remnant livers in association with the downregulation of HMGB1 protein. The ratio of Ki67-positive hepatocytes at 48 hours after 70% hepatectomy was significantly improved. Mean hepatocyte size was significantly reduced and cyclin-dependent kinase inhibitor 1 expression was significantly attenuated.
CONCLUSIONS: Anti-HMGB1 mAb ameliorated IRI and improved the mode of liver regeneration after IRI followed by 70% hepatectomy in rats. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjsurg.2015.06.025

Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy

Masahiro Sugihara, Hiroshi Sadamori, Masahiro Nishibori, Yasuharu Sato, Hiroshi Tazawa, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Kyotaro Ohno, Takeshi Nagasaka, Tadashi Yoshino, Hideo Kohka Takahashi, Takahito Yagi, Toshiyoshi Fujiwara

AMERICAN JOURNAL OF SURGERY 211 ( 1 ) 179 - 188 2016.1

Language：English Publisher：EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC

BACKGROUND: The purpose of this study is to determine the effects of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) on ischemia/reperfusion injury (IRI) and the mode of liver regeneration.
METHODS: Rats underwent 70% hepatectomy with IRI caused by clamping the hepatoduodenal ligament for 20 minutes, followed by the administration of anti-HMGB1 mAb immediately before declamping the hepatoduodenal ligament. Five animals were used for each time point. We then evaluated IRI, regeneration parameters and the status of HMGB1 in remnant livers.
RESULTS: The anti-HMGB1 mAb significantly ameliorated the degree of IRI in the remnant livers in association with the downregulation of HMGB1 protein. The ratio of Ki67-positive hepatocytes at 48 hours after 70% hepatectomy was significantly improved. Mean hepatocyte size was significantly reduced and cyclin-dependent kinase inhibitor 1 expression was significantly attenuated.
CONCLUSIONS: Anti-HMGB1 mAb ameliorated IRI and improved the mode of liver regeneration after IRI followed by 70% hepatectomy in rats. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjsurg.2015.06.025

Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, Hoffman RM

Cell Cycle DOI: 10.1080/15384101.2016.1220461 2016

Adenoviral targeting of malignant melanoma for fluorescenceguided surgery prevents recurrence in orthotopic nude-mouse models

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

Oncotarget 7 ( 14 ) 18558 - 18572 2016

Language：English Publisher：Impact Journals LLC

Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing.

DOI： 10.18632/oncotarget.6670

Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms

Kazuhiro Yoshida, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Keisuke Kimura, Fumitaka Taniguchi, Tomokazu Fuji, Kunitoshi Shigeyasu, Yoshiko Mori, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

Journal of Cancer Research and Clinical Oncology, Zeitschrift fur Krebsforschung und Klinische Onkologie, Zeitschrift fur Krebsforschung 1 - 13 2016

Surgical outcome of patients undergoing pancreaticoduodenectomy

Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Kenta Sui, Tomokazu Fuji, Toshiyoshi Fujiwara

Acta Medica Okayama, Acta. Medica Okayama, Acta medicinae Okayama, Acta medica Okayama 70 ( 3 ) 197 - 204 2016

A case of right-sided Bochdalek hernia incidentally diagnosed in a gastric cancer patient

Kikuchi S, Nishizaki M, Kuroda S, Kagawa S, Fujiwara T

BMC Surg 16 ( 34 ) doi: 10.1186/s12893-016-0145-2 2016

Iron depletion enhances the effect of sorafenib in hepatocarcinoma

Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Kazuhiro Nouso, Akihiro Matsukawa, Kazuhide Yamamoto, Toshiyoshi Fujiwara

CANCER BIOLOGY & THERAPY 17 ( 6 ) 648 - 656 2016

Language：English Publisher：TAYLOR & FRANCIS INC

Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar (R)) and/or deferasirox (EXJADE (R)) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

DOI： 10.1080/15384047.2016.1177677

Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Shuya Yano, Kiyoto Takehara, Ming Zhao, Yuying Tan, Qinghong Han, Shukuan Li, Michael Bouvet, Toshiyoshi Fujiwara, Robert, M. Hoffman

Cell Cycle 1 - 9 2016

Efficient detection of human circulating tumor cells without significant production of false-positive cells by a novel conditionally replicating adenovirus

Sakurai F, Narii N, Tomita K, Togo S, Takahashi K, Machitani M, Tachibana M, Ouchi M, Katagiri N, Urata Y, Fujiwara T, Mizuguchi H

Mol. Ther. Methods Clin. Dev 3 ( 16001 ) 2016

肝移植医療を地域と大学が一体としてまとめ上げた実績とさらなる発展

八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 渡辺信之, 高木弘誠, 須井健太, 藤原俊義, 高木章乃夫, 吉田真理, 保田裕子, 森松博史

肝胆膵 72 ( 3 ) 481 - 487 2016

Behçet's disease complicated by ileocecal and esophageal perforation

Tsukumo Yuta, Kawamoto Kazuyuki, Takagi Kosei, Chin Kai, Matsuba Yuri, Nagahisa Yoshio, Okabe Michio, Shirakawa Yasuhiro, Itoh Tadashi, Fujiwara Toshiyoshi

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 128 ( 1 ) 27 - 32 2016

Language：Japanese Publisher：Okayama Medical Association

A 36-year-old Japanese man known to have incomplete Behçet's disease (oral aphthous ulcers, genital ulcers, skin lesions, and esophageal and ileocecal ulcers) was admitted to our hospital in January 2011 for abdominal pain. We administered corticosteroids and immunosuppressants. Two months later, we performed an ileocecal resection to control gastrointestinal bleeding from the ileocecal ulcers. High fever persisted after this surgery, and upper gastrointestinal endoscopy demonstrated ulcer penetration between the lower and abdominal esophagus. Eighteen days after the initial ileocecal resection, we performed a lower esophagus resection, gastric tube reconstruction and enterostomy, during which we confirmed a 5-mm-dia. perforated site at the posterior wall of the abdominal esophagus. Postoperative anastomotic leakage and empyema occurred, but they were relieved by thoracic drainage and empyema dissection.

DOI： 10.4044/joma.128.27

Other Link： http://ousar.lib.okayama-u.ac.jp/metadata/54077

Therapeutic efficacy in vivo of a telomerase-dependent adenovirus in an orthotopic model of chemotherapy-resistant human stomach carcinomatosis peritonitis visualized with cell cycle color coding FUCCI imaging

Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, Hoffman RM

Journal of Cellular Biochemistry doi: 10.1002/jcb.25593 2016

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Kenjiro Kumano, Hitomi Nishinakamura, Toshiyuki Mera, Takeshi Itoh, Hiroyuki Takahashi, Toshiyoshi Fujiwara, Shohta Kodama

ISLETS 8 ( 5 ) 145 - 155 2016

Language：English Publisher：TAYLOR & FRANCIS INC

Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival. BALB/c islets pretreated with papain were transplanted into C57BL/6J mice as an acute allorejection model. Treatment with 1mg/mL papain significantly prolonged islet allograft survival. In vitro, to determine the inhibitory effect on T cell-mediated alloreactions, we performed lymphocyte proliferation assays and mixed lymphocyte reactions. Host T cell activation against allogenic islet cells was remarkably suppressed by pretreatment of donor islet cells with 10mg/mL papain. Flow cytometric analysis was also performed to investigate the effect of papain treatment on the expression of MHC class I on islets. One or 10mg/mL papain treatment reduced MHC class I expression on the islet cell surface. Pretreatment of donor islets with papain suppresses MHC class I-mediated allograft rejection in mice and contributes to prolongation of islet allograft survival without administration of systemic immunosuppressants. These results suggest that pretreatment of human donor islets with papain may reduce the immunogenicity of the donor islets and minimize the dosage of systemic immunosuppressants required in a clinical setting.

DOI： 10.1080/19382014.2016.1223579

Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models

Yano S, Takehara K, Tazawa H, Kishimoto H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

Journal of Cellular Biochemistry doi: 10.1002/jcb.25735 2016

胃癌術後肝転移再発に対してThird-LineのCPT-11が奏効し長期生存を得た1 例

菊地覚次, 西﨑正彦, 黒田新士, 香川俊輔, 藤原俊義

癌と化学療法 43 ( 12 ) 2219 - 2221 2016

Language：Japanese Publisher：(株)癌と化学療法社

症例は63歳、男性。早期胃癌(pT1bN0M0、pStage IA)術後20ヵ月のCTにて多発肝転移再発を認め、first-lineとしてS-1+CDDP療法2コース施行後、腫瘍は増大し、second-lineとしてnab-PTX6コース施行するも腫瘍増大、肝酵素上昇、体重減少と全身状態の悪化を認めた。しかし、third-lineのCPT-11が奏効し、肝酵素も正常化、体重も増加し全身状態、ADLの改善も認め、8ヵ月PRを維持した。CPT-11合計17コース施行後に腫瘍が増大し、その後S-1+oxaliplatin療法、DTX、再度CPT-11、ramucirumab投与を行い、再発後31ヵ月原病死された。胃癌肝転移に対してCPT-11はkey drugになる可能性があり、また予後延長には胃癌に有効なkey drugをすべて使い切るマネージメントが重要と考えられた。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00296&link_issn=&doc_id=20161222480266&doc_link_id=%2Fab8gtkrc%2F2016%2F004312%2F266%2F2219-2221%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2016%2F004312%2F266%2F2219-2221%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Shuya Yano, Kiyoto Takehara, Ming Zhao, Yuying Tan, Qinghong Han, Shukuan Li, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 15 ( 13 ) 1715 - 1723 2016

Language：English Publisher：TAYLOR & FRANCIS INC

We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G(2)/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G(0)/G(1) to S/G(2)/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G(2), shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G(2) phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of decoy, trap and shoot chemotherapy.

DOI： 10.1080/15384101.2016.1181240

Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

Daisuke Uchida, Akinobu Takaki, Hisashi Ishikawa, Yasuko Tomono, Hironari Kato, Koichiro Tsutsumi, Naofumi Tamaki, Takayuki Maruyama, Takaaki Tomofuji, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Hiroshi Matsushita, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Kazuhiro Nouso, Ryuichi Yoshida, Yuzo Umeda, Susumu Shinoura, Takahito Yagi, Toshiyoshi Fujiwara, Manabu Morita, Masaki Fukushima, Kazuhide Yamamoto, Hiroyuki Okada

FREE RADICAL RESEARCH 50 ( 7 ) 732 - 743 2016

Language：English Publisher：TAYLOR & FRANCIS LTD

Background: Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
Methods: We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
Results: Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. L-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
Conclusion: Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent L-carnitine is a good candidate to control oxidative stress conditions.

DOI： 10.3109/10715762.2016.1172071

An extended retroperitoneal emphysema with diversion colitis after colonoscopy

Tetsuya Kagawa, Shin Nakatani, Hiroyuki Kishimoto, Yoshitaka Kondo, Toshiko Mori, Takeshi Nagasaka, Toshiyoshi Fujiwara

Japanese Journal of Gastroenterological Surgery 49 ( 8 ) 804 - 811 2016

Language：Japanese Publisher：Japanese Society of Gastroenterological Surgery

A 68-year-old man with a history of intersphincteric resection and transverse colostomy for rectal cancer underwent diagnostic colonoscopy as a post-operative follow up. Colonoscopy revealed diversion colitis of the sigmoid colon. Two hours after the examination, the patient complained of mild abdominal pain. Blumberg sign was negative and no remarkable changes were observed, but abdominal pain did not improve for 6 hours. A CT scan showed retropneumoperitoneum, pneumomediastinum, subcutaneous emphysema and pneumatosis intestinalis of the sigmoid colon without any evidence of perforation. We diagnosed retroperitoneal emphysema with diversion colitis after colonoscopy and the patient was admitted to our hospital. We decided on a conservative treatment method because of the lack of peritonitis and good general condition. The clinical course was uneventful and he was discharged 11 days after the initial observation. Retroperitoneal emphysema is a very rare complication that occurs after colonoscopy. We report our case with a literature review of 25 cases of retroperitoneal emphysema after colonoscopy in Japan.

DOI： 10.5833/jjgs.2015.0141

Incisional hernia repair after wide excision of the iliac bone

Tsukuda Kazunori, Asano Hiroaki, Mandai Yasuhiro, Fujiwara Toshiyoshi

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 128 ( 2 ) 117 - 120 2016

Language：Japanese Publisher：Okayama Medical Association

The patient was a 46-year old Japanese female who had undergone wide excision of the iliac bone and hip transposition at our institute's orthopedics department 2 years earlier. She presented with a growing incisional hernia and was transferred to our gastroenterological surgery department for surgical treatment. We planned a mesh repair for the incisional hernia, which protruded over the right iliac bone. The dimensions of the abdominal defect were 15×9 cm, and we used prolene mesh to repair the defect. The mesh was fixed at the inner part of the iliac bone, folded back at the iliac horn and fixed to the abdominal oblique muscles. The postoperative course was smooth, and recurrence was not seen at 3.5 years after the operation. An incisional hernia as seen in this patient's case is very rare, but we found that the underlay technique and prolene mesh were very useful for the three-dimensional hernia repair.

DOI： 10.4044/joma.128.117

Other Link： http://search.jamas.or.jp/link/ui/2016396172

癌関連線維芽細胞が食道癌の浸潤と転移に及ぼす影響の検証

賀島肇, 野間和広, 桂佑貴, 加藤卓也, 大原利章, 田澤大, 白川靖博, 香川俊輔, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 27th 2016

腹腔鏡下噴門側胃切除

西﨑正彦, 藤原俊義

日本外科学会雑誌 117 ( 6 ) 543 - 546 2016

腹臥位胸腔鏡下食道亜全摘術

白川靖博, 野間和広, 金谷信彦, 岡田剛, 前田直見, 田辺俊介, 藤原俊義

消化器外科 39 ( 9 ) 1223 - 1235 2016

Molecular theranostics for gastrointestinal cancer：分子イメージングと治療の融合

藤原俊義

JSMI Report 10 ( 1 ) 7 - 11 2016

「臨床研究の基礎と実践」によせて

藤原俊義

日本外科学会雑誌 117 ( 6 ) 597 - 597 2016

テロメラーゼ標的化がん治療・診断用アデノウイルス

田澤大, 香川俊輔, 重安邦俊, 藤原俊義

実験医学 34 ( 1 ) 13 - 18 2016

いま「外科臨床研究」に求められていること

藤原俊義

臨床外科 71 ( 5 ) 524 - 525 2016

胆管の外科解剖

八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 藤原俊義

手術 70 ( 4 ) 347 - 354 2016

腫瘍融解ウイルス療法の臨床開発

藤原俊義

医学のあゆみ 258 ( 5 ) 503 - 508 2016

多視点3D映像システムによる次世代の手術解剖教育

信岡大輔, 八木孝仁, 近藤喜太, 篠浦先, 楳田祐三, 吉田龍一, 渡辺信之, 杭瀬崇, 藤智和, 高木弘誠, 藤原俊義

日本消化器外科学会雑誌(Web) 49 ( Supplement2 ) 2016

当院における膵頭十二指腸切除術の治療成績

高木弘誠, 八木孝仁, 吉田龍一, 藤智和, 杭瀬崇, 渡辺信之, 信岡大輔, 楳田祐三, 篠浦先, 藤原俊義

日本消化器外科学会雑誌(Web) 49 ( Supplement2 ) 2016

頭頚部および胸部外科手術後の難治性リンパ漏に対するリンパ管造影の経験

岡田剛, 野間和広, 金谷信彦, 前田直見, 田邊俊介, 白川靖博, 藤原俊義

日本食道学会学術集会抄録集(CD-ROM) 70th 2016

胸腔鏡下食道亜全摘術後に発症した術後リンパ瘻に対し,腹臥位胸腔鏡下胸管結紮術により治療し得た一例

土生智大, 白川靖博, 升田智也, 前田直見, 二宮卓之, 田邊俊介, 野間和広, 櫻間教文, 藤原俊義

日本内視鏡外科学会雑誌 21 ( 7 (CD-ROM) ) 2016

食道切除術後胃管再建におけるICG蛍光法による胃管血流評価の有用性

岡田剛, 野間和広, 金谷信彦, 前田直見, 田邊俊介, 白川靖博, 藤原俊義

日本消化器外科学会雑誌(Web) 49 ( Supplement1 ) 2016

Multimodality preoperative treatment based on DCF chemotherapy for highly advanced esophageal cancer

田邊俊介, 白川靖博, 金谷信彦, 岡田剛, 前田直見, 櫻間教文, 野間和広, 西崎正彦, 香川俊輔, 藤原俊義

日本消化器外科学会雑誌(Web) 49 ( Supplement1 ) 2016

胃腫瘍に対するClosed-LECSの定型化と展望

西崎正彦, 菊地覚次, 黒田新士, 加藤大, 田邊俊介, 野間和広, 香川俊輔, 白川靖博, 岡田裕之, 藤原俊義

先進内視鏡治療研究会 10th 2016

Acquired Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Metastatic Colorectal Cancer

谷口文崇, 永坂岳司, 藤智和, 母里淑子, 岸本浩行, 河合毅, 楳田祐三, 藤原俊義

日本消化器外科学会雑誌(Web) 49 ( Supplement1 ) 2016

リンチ症候群における遺伝子変異の特徴とスクリーニング,PD-1を含めた治療標的

永坂岳司, 谷口文崇, 母里淑子, 藤原俊義

日本臨床腫瘍学会学術集会(CD-ROM) 14th 2016

遺伝子変異情報を考慮したStage IV大腸癌に対する予後の検討及び治療戦略の構築

永坂岳司, 母里淑子, 岸本浩行, 神原健, 河合毅, 中谷紳, 嶋村廣視, 富岡憲明, 森谷行利, 瀧上隆夫, 佃和憲, 藤原俊義

日本大腸肛門病学会雑誌(Web) 69 2016

A Case-matched Comparative Study of Laparoscopic and Open Total Proctocolectomy for Ulcerative Colitis

Ryo Inada, Takeshi Nagasaka, Yoshitaka Kondo, Ayako Watanabe, Toshiaki Toshima, Nobuhito Kubota, Satoru Kikuchi, Michihiro Ishida, Shinji Kuroda, Yoshiko Mori, Hiroyuki Kishimoto, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 69 ( 5 ) 267 - 273 2015.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

The aim of this single-institution, retrospective, observational case-control study was to evaluate the safety and feasibility of laparoscopic proctocolectomy (PC) for ulcerative colitis (VC), by comparing it with a case-control series of open PC. Twenty UC patients who underwent laparoscopic PC were retrospectively compared with the open PC group of 12 patients matched for age, sex, and urgency of the operation. In the laparoscopic PC group, the operative time was significantly longer, but the amount of blood loss was significantly smaller. The open PC patients underwent an intraoperative blood transfusion significantly more often, and the serum C-reactive protein level on the first postoperative day was significantly higher in the open PC group. In the laparoscopic PC group, the rate of severe postoperative morbidities, grades 3 and 4 on the Clavien-Dindo classification, was significantly lower, and the median length of hospital stay was significantly shorter. Laparoscopic PC for patients with UC showed superior perioperative outcomes to open PC, except for longer operative time.

DOI： 10.18926/AMO/53672

Neoadjuvant Chemotherapy with or without Concurrent Hormone Therapy in Estrogen Receptor-Positive Breast Cancer: NACED-Randomized Multicenter Phase II Trial

Kumi Sugiu, Takayuki Iwamoto, Catherine M. Kelly, Naoki Watanabe, Takayuki Motoki, Mitsuya Itoh, Shoichiro Ohtani, Kenji Higaki, Takako Imada, Takeshi Yuasa, Masako Omori, Hiroshi Sonobe, Toshiyoshi Fujiwara, Junji Matsuoka

ACTA MEDICA OKAYAMA 69 ( 5 ) 291 - 299 2015.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Although in the neoadjuvant setting for estrogen receptor (ER)-positive breast cancers, chemotherapy or hormone therapy alone does not result in satisfactory tumor response, it is unknown whether concurrent chemo-endocrine therapy is superior to chemotherapy alone in clinical outcomes. We conducted a randomized phase II trial to test the responses of ER-positive patients to concurrent administration of chemo-endocrine therapy in the neoadjuvant setting. Women with stage ER-positive, invasive breast cancer (n=28) received paclitaxel followed by fluorouracil, epirubicin, cyclophosphamide (T-FEC) and were randomized to receive concurrent chemo-endocrine therapy consisting of goserelin administered subcutaneously for premenopausal women or an aromatase inhibitor for post-menopausal women. The primary endpoint was the pathological complete response (pCR) rate after neoadjuvant therapy. Twenty-eight patients were randomized. There were no significant differences in pCR rate between the concurrent group (12.5%; 2/16) and the chemotherapy alone group (8.3%; 1112). Tumor size after therapy was significantly reduced in the concurrent therapy group (p=0.035), but not in the chemotherapy-alone group (p=0.622). Neoadjuvant chemotherapy with concurrent hormone therapy provided no significant improvement in pCR rate in ER-positive breast cancers. These preliminary results should be followed up by further studies.

DOI： 10.18926/AMO/53675

宿主正常細胞である癌関連線維芽細胞を標的とした新たな食道癌治療法の開発

野間和広, 賀島肇, 二宮卓之, 勝部亮一, 渡邉伸一郎, 大原利章, 田澤大, 香川俊輔, 白川靖博, 藤原俊義

癌と化学療法 42 ( 10 ) 1228 - 1230 2015.10

Language：Japanese Publisher：(株)癌と化学療法社

近年の分子細胞生化学の発展により、分子標的治療薬によって飛躍的に予後改善を認める癌腫もでてきている。また、bevacizumabの台頭にみられるように、がん微小環境を制御することでより抗腫瘍効果を上げる例もでてきており、新しい可能性を示唆している。癌とがん微小環境の相互作用については以前より多く報告されており、その中心的な役割を担っているのが癌関連線維芽細胞(cancer-associated fibroblasts:CAFs)といわれている。以前よりわれわれは、食道癌の進展におけるがん微小環境の強い関与を推測し、特にCAFの作用に注目し分子標的となり得るシグナルの解析を行ってきた。しかしながら、CAFの単一のシグナル阻害のみでは癌の治療においては不十分な可能性が考えられた。現在までに多くのCAF細胞におけるシグナルを標的とした治療法が提案されてきたが、未だ十分な結果を得ていない。光線免疫療法は、2011年にMitsunagaらにて発表された近赤外線光を用いた標的分子特異的癌治療である。われわれは、その細胞特異性に殺傷できるシステムに注目し、現在CAFそのものを制御すべくCAFに対する光線化学療法の開発、またその効果を検討している。今後検討結果を随時報告する予定である。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00296&link_issn=&doc_id=20151027380020&doc_link_id=%2Fab8gtkrc%2F2015%2F004210%2F021%2F1228-1230%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2015%2F004210%2F021%2F1228-1230%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

HER2-targeted gold nanoparticles produce potent antitumor effects on human gastric cancer cells

Tetsushi Kubota, Shinji Kuroda, Katsuyuki Aoyama, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

Differentiated gastric cancer cells have a potential to induce cancer-associated fibroblasts

Yuncheng Li, Hiroshi Tazawa, Nishizaki Masahiko, Yuuri Hashimoto, Naoto Hori, Ryoichi Katsube, Shinji Kuroda, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

Preclinical study of telomerase-specific p53 tumor suppressor gene overexpression in human scirrhous gastric cancer cells with different p53 status

Naoto Hori, Hiroshi Tazawa, Masahiko Nishizaki, Satoru Kikuchi, Shuya Yano, Michihiro Ishida, Megumi Watanabe, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

A novel photoimmunotherapy targeting cancer-associated fibroblasts (CAFs) overcomes therapeutic resistance in human esophageal cancer

Ryoichi Katsube, Kazuhiro Noma, Shinichiro Watanabe, Shinichi Urano, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

Phase I/II trial of endoscopic intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, with radiation in elderly esophageal cancer patients

Shunsuke Tanabe, Hiroshi Tazawa, Shunsuke Kagawa, Kazuhiro Noma, Kiyoto Takehara, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

A novel tumor-specific oncolytic biological therapy against invasive pancreatic cancer

Takeshi Koujima, Hiroshi Tazawa, Naoto Hori, Shuta Tamura, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway

Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Takeshi Koujima, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells: a preliminary clinical study as a potential clinical biomarker

Megumi Watanabe, Shunsuke Kagawa, Kazuya Kuwata, Michihiro Ishida, Yuuri Hashimoto, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

CANCER RESEARCH 75 2015.8

Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability

Keisuke Toda, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Takashi Kawai, Tomokazu Fuji, Fumitaka Taniguchi, Kazuya Yasui, Nobuhito Kubota, Yuko Takehara, Hiroshi Tazawa, Shunsuke Kagawa, Dong-Sheng Sun, Naoshi Nishida, Ajay Goel, Toshiyoshi Fujiwara

CLINICAL EPIGENETICS 7 doi:10.1186/s13148-015-0096-y 2015.7

Language：English Publisher：BIOMED CENTRAL LTD

Background: The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis.
Results: In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers.
Conclusions: Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.

DOI： 10.1186/s13148-015-0096-y

Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors

Kazuko Koike, Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Tetsuya Yasunaka, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Sato, Daisuke Nobuoka, Masashi Utsumi, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Toshiyoshi Fujiwara, Kazuhide Yamamoto

TRANSPLANTATION 99 ( 7 ) 1447 - 1454 2015.7

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background. Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2. Methods. The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines. Results. The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity. Conclusions. The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

DOI： 10.1097/TP.0000000000000572

Experimental Curative Fluorescence-guided Surgery of Highly Invasive Glioblastoma Multiforme Selectively Labeled With a Killer-reporter Adenovirus

Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Michael Bouvet, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

MOLECULAR THERAPY 23 ( 7 ) 1182 - 1188 2015.7

Language：English Publisher：NATURE PUBLISHING GROUP

Fluorescence-guided surgery (FGS) of cancer is an area of intense current interest. However, although benefits have been demonstrated with FGS, curative strategies need to be developed. Glioblastoma multiforme (GBM) is one of the most invasive of cancers and is not totally resectable using standard bright-light surgery (BLS) or current FGS strategies. We report here a curative strategy for FGS of GBM. In this study, telomerase-dependent adenovirus OBP-401 infection brightly and selectively labeled GBM with green fluorescent protein (GFP) for FGS in orthotopic nude mouse models. OBP-401-based FGS enabled curative resection of GBM without recurrence for at least 150 days, compared to less than 30 days with BLS.

DOI： 10.1038/mt.2015.63

Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery

S. Yano, Y. Hiroshima, A. Maawy, H. Kishimoto, A. Suetsugu, S. Miwa, M. Toneri, M. Yamamoto, M. H. G. Katz, J. B. Fleming, Y. Urata, H. Tazawa, S. Kagawa, M. Bouvet, T. Fujiwara, R. M. Hoffman

CANCER GENE THERAPY 22 ( 7 ) 344 - 350 2015.7

Language：English Publisher：NATURE PUBLISHING GROUP

Precise fluorescence-guided surgery (FGS) for pancreatic canter has the potential to greatly improve the outcome in this recalcitrant disease. To achieve this goal, we have used genetic reporters to-color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic Mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX Model enabled FGS to to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence; which bright-light surgery or single-color FGS could not. FGS, with color-coded canter and stroma cells has important potential for improving the outcome of recalcitrant-cancer surgery.

DOI： 10.1038/cgt.2015.26

緩和医療乳癌患者スクリーニングシートによる診断時からの緩和医療の導入

松岡順治, 元木崇之, 岩本高行, 高下典子, 露無佑子, 土井原博, 南大輔, 藤原俊義

日本乳癌学会総会プログラム抄録集 23回 295 - 295 2015.7

Prone-Position Thoracoscopic Ligation of the Thoracic Duct for Chyle Leak Following Radical Neck Dissection in a Patient with a Right Aortic Arch

Yasuhiro Shirakawa, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Naoaki Maeda, Shunsuke Tanabe, Shunsuke Kagawa, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 69 ( 3 ) 173 - 176 2015.6

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

A chyle leak can occur as a complication after neck or chest surgery. Such a leak prolongs the hospital stay and is sometimes life-threatening. The treatment options are conservative management, interventional radiologic embolization, and surgery. Thoracoscopic ligation of the thoracic duct has emerged as a promising and definitive treatment The case of a 65-year-old Japanese male patient with a rare congenital right aortic arch (type IIIB1 of Edward's classification) and a severe chyle leak that occurred after a total pharyngolaryngo-esophagectomy (TPLE) is described. The chyle leak was successfully managed by thoracoscopic ligation of the thoracic duct via a left-side approach with the patient in the prone position.

DOI： 10.18926/AMO/53524

Heterogeneous cell-cycle behavior in response to UVB irradiation by a population of single cancer cells visualized by time-lapse FUCCI imaging

Shinji Miwa, Shuya Yano, Hiroaki Kimura, Mako Yamamoto, Makoto Toneri, Takashi Murakami, Katsuhiro Hayashi, Norio Yamamoto, Toshiyoshi Fujiwara, Hiroyuki Tsuchiya, Robert M. Hoffman

CELL CYCLE 14 ( 12 ) 1932 - 1937 2015.6

Language：English Publisher：TAYLOR & FRANCIS INC

The present study analyzed the heterogeneous cell-cycle dependence and fate of single cancer cells in a population treated with UVB using a fluorescence ubiquitination-based cell-cycle (FUCCI) imaging system. HeLa cells expressing FUCCI were irradiated by 100 or 200 J/m(2) UVB. Modulation of the cell-cycle and apoptosis were observed by time-lapse confocal microscopy imaging every 30min for 72h. Correlation between cell survival and factors including cell-cycle phase at the time of the irradiation of UVB, mitosis and the G(1)/S transition were analyzed using the Kaplan-Meier method along with the log rank test. Time-lapse FUCCI imaging of HeLa cells demonstrated that UVB irradiation induced cell-cycle arrest in S/G(2)/M phase in the majority of the cells. The cells irradiated by 100 or 200 J/m(2) UVB during G(0)/G(1) phase had a higher survival rate than the cells irradiated during S/G(2)/M phase. A minority of cells could escape S/G(2)/M arrest and undergo mitosis which significantly correlated with decreased survival of the cells. In contrast, G(1)/S transition significantly correlated with increased survival of the cells after UVB irradiation. UVB at 200 J/m(2) resulted in a greater number of apoptotic cells.

DOI： 10.1080/15384101.2015.1033598

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer

Kunitoshi Shigeyasu, Takeshi Nagasaka, Yoshiko Mori, Naosuke Yokomichi, Takashi Kawai, Tomokazu Fuji, Keisuke Kimura, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

PLOS ONE 10 ( 6 ) e0130409 2015.6

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Background
To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown.
Methods
This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1methylation status in relation to overall survival (OS).
Results
By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis.
Conclusions
CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.

DOI： 10.1371/journal.pone.0130409

Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma

Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Fuminari Uehara, Hiroshi Tazawa, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 6 ( 15 ) 13133 - 13148 2015.5

Language：English Publisher：IMPACT JOURNALS LLC

Fluorescence-guided surgery (FGS) of cancer is an area of intense interest. However, FGS of cancer has not yet been shown to be curative due to residual microscopic disease. Human fibrosarcoma HT1080 expressing red fluorescent protein (RFP) was implanted orthotopically in the quadriceps femoris muscle of nude mice. The tumor-bearing mice were injected with high and low-dose telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401, which labeled the tumor with GFP. Fluorescence-guided surgery (FGS) or bright light surgery (BLS) was then performed. OBP-401 could label soft-tissue sarcoma (STS) with GFP in situ, concordant with RFP. OBP-401-based FGS resulted in superior resection of STS in the orthotopic model of soft-tissue sarcoma, compared to BLS. High-dose administration of OBP-401 enabled FGS without residual sarcoma cells or local or metastatic recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. High-dose OBP-401 based-FGS improved disease free survival (p = 0.00049) as well as preserved muscle function compared with BLS. High-dose OBP-401-based FGS could cure STS, a presently incurable disease. Since the parent virus of OBP-401, OBP-301, has been previously proven safe in a Phase I clinical trial, it is expected the OBP-401-FGS technology described in the present report should be translatable to the clinic in the near future.

Effect of methionine-depletion via methioninase-treatment on cancer cells in S/G2 phase and chemosensitivity.

Shuya Yano, Shukuan Li, Qinghong Han, Yuying Tan, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

JOURNAL OF CLINICAL ONCOLOGY 33 ( 15 ) 2015.5

MicroRNA as a molecular target for gastrointestinal cancers

Hiroshi Tazawa, Takeshi Nagasaka, Shunsuke Kagawa, Toshiyoshi Fujiwara

TRANSLATIONAL GASTROINTESTINAL CANCER 4 ( 3 ) 219 - 235 2015.5

Language：English Publishing type：Book review, literature introduction, etc. Publisher：AME PUBL CO

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally suppress the expression of many target genes, thereby contributing to the modulation of diverse cellular fates in tumor biology. Recent accumulating evidences have demonstrated that aberrant expression of miRNAs is highly associated with tumor initiation, progression and metastasis in various types of cancers including gastrointestinal (GI) cancers. Exploration of precise miRNA-based gene regulatory networks in the pathogenesis of GI cancers will provide important information for the development of novel anticancer strategies aimed at normalizing the critical miRNAs that are deregulated in GI cancers. Recent reports using clinical samples have shown the potential of upregulation of oncogenic miR-21 and of downregulation of the tumor-suppressive miR-34 family as novel molecular biomarkers for the diagnostic and prognostic prediction of GI cancers. In this review, we have focused on the functional roles of these two cancer-related miRNAs, miR-21 and miR-34, that are commonly deregulated during the development and progression of GI cancers. Moreover, the therapeutic potential of miRNA-targeting anticancer therapy is discussed for clinical application as novel anticancer therapy for GI cancers.

DOI： 10.3978/j.issn.2224-4778.2015.04.01

Aggressive Multimodality Treatment for Advanced Rectal Cancer

Ryo Inada, Takeshi Nagasaka, Toshiaki Toshima, Yoshiko Mori, Yoshitaka Kondo, Hiroyuki Kishimoto, Takao Hiraki, Taihei Oshiro, Yukihide Kanemitsu, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 69 ( 2 ) 113 - 118 2015.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

A case of advanced rectal cancer treated by aggressive local and systemic treatment who has survived more than 7 years from initial recurrence is presented. A 55-year-old woman was diagnosed with advanced lower rectal cancer and underwent a low anterior resection with complete removal of all regional lymph nodes and total mesorectal excision. The tumor was diagnosed as a moderately differentiated adenocarcinoma, pStage IIIB (T3, N2a, M0). Twenty-six months after the initial surgery, local recurrence in the pelvis was detected by computed tomography, and total pelvic exenteration with distal sacrectomy (TPES) was performed after systemic chemotherapy with a molecular-targeted drug. Six months after the TPES, multiple lung metastases were detected. Consequently, the patient underwent radiofrequency ablation (RFA) and chemotherapy. The disease has since been controlled for 38 months. As volume control is essential for cancer treatment, it may be important to combine appropriate local therapy with systemic therapy to metastatic or recurrent sites in order to achieve much longer disease control.

Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics

Kunitoshi Shigeyasu, Hiroshi Tazawa, Yuuri Hashimoto, Yoshiko Mori, Masahiko Nishizaki, Hiroyuki Kishimoto, Takeshi Nagasaka, Shinji Kuroda, Yasuo Urata, Ajay Goel, Shunsuke Kagawa, Toshiyoshi Fujiwara

GUT 64 ( 4 ) 627 - 635 2015.4

Language：English Publisher：BMJ PUBLISHING GROUP

Background Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs.
Methods We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan).
Results Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial-mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer.
Conclusions This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.

DOI： 10.1136/gutjnl-2014-306957

Correlation of Computed Tomography Imaging Features and Pathological Features of 41 Patients with Pancreatic Neuroendocrine Tumors

Masashi Utsumi, Yuzo Umeda, Kosei Takagi, Kuise Takashi, Daisuke Nobuoka, Ryuichi Yoshida, Susumu Shinoura, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara

HEPATO-GASTROENTEROLOGY 62 ( 138 ) 441 - 446 2015.3

Language：English Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background:/Aims: Pancreatic neuroendocrine tumors (PNET) are relatively rare. Here, we present clinical and pathological characteristics of PNETs to show a relationship between computed tomography (CT) imaging and the 2010 World Health Organization (WHO) classification. Methodology: We retrospectively reviewed the records of 41 PNET patients who were treated between 2002 and 2012. All tumors were classified as neuroendocrine tumor (NET) grade 1 (121), NET grade 2 (G2), or neuroendocrine carcinoma (NEC) grade 3 (G3) on the basis of the 2010 WHO classification system. Results: Twenty-five tumors were classified as G1, 11 as G2, and five as G3. Mean sizes of the G1, G2 and G3 tumors were 1.84 +/- 0.54, 4.90 +/- 0.84, and 5.62 +/- 1.18 cm, respectively, (P < 0.01). A PNET is typically hypervascular and exhibits contrast enhancement on enhanced CT. Higher percentage of G1 tumors demonstrated typical imaging and showed a significantly greater distinct mass compared with G2 and G3 tumors. Conclusions: Although PNET has many imaging features that appear on CT, G2 and G3 tumors often show atypical imaging features, particularly with large sizes and/or ill-defined features, when compared with G1 tumors. If a PNET has atypical imaging features, possibility of malignancy should be considered.

DOI： 10.5754/hge14388

Cancer cells mimic in vivo spatial-temporal cell-cycle phase distribution and chemosensitivity in 3-dimensional Gelfoam (R) histoculture but not 2-dimensional culture as visualized with real-time FUCCI imaging

Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminaru Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 14 ( 6 ) 808 - 819 2015.3

Language：English Publisher：TAYLOR & FRANCIS INC

The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We previously reported monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor, intravitally in live mice, using a fluorescence ubiquitination-based cell-cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after cessation of chemotherapy. These results suggested why most drugs currently in clinical use, which target cancer cells in S/G(2)/M, are mostly ineffective on solid tumors. In the present report, we used FUCCI imaging and Gelfoam (R) collagen-sponge-gel histoculture, to demonstrate in real time, that the cell-cycle phase distribution of cancer cells in Gelfoam (R) and in vivo tumors is highly similar, whereby only the surface cells proliferate and interior cells are quiescent in G(0)/G(1). This is in contrast to 2D culture where most cancer cells cycle. Similarly, the cancer cells responded similarly to toxic chemotherapy in Gelfoam (R) culture as in vivo, and very differently than cancer cells in 2D culture which were much more chemosensitive. Gelfoam (R) culture of FUCCI-expressing cancer cells offers the opportunity to image the cell cycle of cancer cells continuously and to screen for novel effective therapies to target quiescent cells, which are the majority in a tumor and which would have a strong probability to be effective in vivo.

DOI： 10.1080/15384101.2014.1000685

ARID1A expression in gastric adenocarcinoma: Clinicopathological significance and correlation with DNA mismatch repair status

Ryo Inada, Shigeki Sekine, Hirokazu Taniguchi, Hitoshi Tsuda, Hitoshi Katai, Toshiyoshi Fujiwara, Ryoji Kushima

WORLD JOURNAL OF GASTROENTEROLOGY 21 ( 7 ) 2159 - 2168 2015.2

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.
METHODS: We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.
RESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6 +/- 9.2 vs 60.4 +/- 11.7, P < 0.001), a female sex (55.3% vs 31.3%, P = 0.004), an antral location (44.7% vs 25.7%, P = 0.021), and a differentiated histology (57.9% vs 39.7%, P = 0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P = 0.022) and lymph node metastasis (83.5% vs 73.7%, P = 0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P < 0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR = 1.36, 95% CI: 1.01-1.84; P = 0.040).
CONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.

DOI： 10.3748/wjg.v21.i7.2159

Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells

Kyoko Shimoyama, Shunsuke Kagawa, Michihiro Ishida, Shinichiro Watanabe, Kazuhiro Noma, Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Shunsuke Tanabe, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

BREAST CANCER RESEARCH AND TREATMENT 149 ( 3 ) 597 - 605 2015.2

Language：English Publisher：SPRINGER

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25 % of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

DOI： 10.1007/s10549-015-3265-y

Prone-position thoracoscopic resection of posterior mediastinal lymph node metastasis from rectal cancer

Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Toshiyoshi Fujiwara

WORLD JOURNAL OF SURGICAL ONCOLOGY 13 ( 45 ) doi:10.1186/s12957-015-0466-0 2015.2

Language：English Publisher：BIOMED CENTRAL LTD

Mediastinal lymph node metastasis from colorectal cancer is rare, and barely any reports have described resection of this pathology. We report herein a successful thoracoscopic resection of mediastinal lymph node metastasis in a prone position. A 65-year-old man presented with posterior mediastinal lymph node metastasis after resection of the primary rectal cancer and metachronous hepatic metastasis. Metastatic lymph nodes were resected completely using thoracoscopic surgery in the prone position, which provided advantages of minimal invasiveness, good surgical field, and reduced ergonomic burden on the surgeon. Thoracoscopic resection in the prone position was thought to have the potential to become the standard procedure of posterior mediastinal tumors.

DOI： 10.1186/s12957-015-0466-0

Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging

Shinji Miwa, Shuya Yano, Hiroaki Kimura, Mako Yamamoto, Makoto Toneri, Yasunori Matsumoto, Fuminari Uehara, Yukihiko Hiroshima, Takashi Murakami, Katsuhiro Hayashi, Norio Yamamoto, Michael Bouvet, Toshiyoshi Fujiwara, Hiroyuki Tsuchiya, Robert M. Hoffman

CELL CYCLE 14 ( 4 ) 621 - 629 2015.2

Language：English Publisher：TAYLOR & FRANCIS INC

Essentially every population of cancer cells within a tumor is heterogeneous, especially with regard to chemosensitivity and resistance. In the present study, we utilized the fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging system to investigate the correlation between cell-cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5M) or cisplatinum (CDDP) (5M) for 3h. Cell-cycle progression and apoptosis were monitored by time-lapse FUCCI imaging for 72h. Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell cycle arrest in S/G(2)/M in almost all the cells, but a subpopulation of the cells could escape the block and undergo mitosis. The subpopulation which went through mitosis subsequently underwent apoptosis, while the cells arrested in S/G(2)/M survived. The present results demonstrate that chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G(2)/M arrest, which can serve in future studies as a visible target for novel agents that kill cell-cycle-arrested cells.

DOI： 10.4161/15384101.2014.991604

The rare BRAF VK600-601E mutation as a possible indicator of poor prognosis in rectal carcinoma - a report of a case

Yoshiko Mori, Takeshi Nagasaka, Hideyuki Mishima, Yuzo Umeda, Ryo Inada, Hiroyuki Kishimoto, Ajay Goel, Toshiyoshi Fujiwara

BMC MEDICAL GENETICS 16 ( 1 ) 10.1186/s12881-015-0144-7 2015.1

Language：English Publisher：BIOMED CENTRAL LTD

Background: The BRAF V600E mutation is reportedly associated with inferior survival among colon cancer patients. Here we report a patient with rectal cancer who carried the novel BRAF mutation VK600-601E, which has analogous molecular functions to those of the conventional BRAF mutation V600E, and may have potential as a prognostic marker for colorectal cancer (CRC).
Case presentation: The present 65-year-old male patient was diagnosed with recurrent rectal adenocarcinoma (stage II by AJCC TNM staging 7th edition) 14 months after surgery and was treated with modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin), radiation, and FOLFIRI (fluorouracil, leucovorin, and irinotecan). The tumor progressed before further treatment could be initiated, resulting in death after 15 months. This survival period was similar to the median overall survival among patients with metastatic CRC and BRAF mutations who were treated with the FOLFIRI regimen with or without cetuximab.
Conclusions: Thus, the BRAF VK600-601E mutation may lead to an aggressive clinical course in CRC patients suffering from rapid progression and potential resistance to multiple therapeutic modalities.

DOI： 10.1186/s12881-015-0144-7

Operative technique of antethoracic esophageal reconstruction with pedicled jejunal flap

Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

ESOPHAGUS 12 ( 1 ) 57 - 64 2015.1

Language：English Publisher：SPRINGER JAPAN KK

Esophageal reconstruction using intestine is often performed for esophageal cancer patients in cases where the stomach cannot be used. We have previously performed reconstruction using ileocolon with supercharge and drainage as our first choice in those cases. However, a less invasive, simpler, and safer reconstructive technique using jejunum without vascular anastomosis has recently become popular at our facility. This study describes the technique of esophageal reconstruction with jejunum, compares the surgical outcomes to those of standard reconstruction using ileocolon, and discusses the clinical significance of this new concept.
Subjects comprised 53 patients (52 males, 1 female) who underwent esophageal reconstruction using jejunum between January 2008 and July 2013. Patient characteristics, technical details, and outcomes were compared with those of 51 subjects who had undergone esophageal reconstruction using ileocolon. When making the pedicled jejunal flap, the first jejunal vascular arcade was preserved, which in most cases allowed it to be pulled up to the cervical region by processing and transection up to the second jejunal vascular branch.
The vascular anastomosis techniques were used in 80.4 % (41/51) of esophageal reconstructions using colon, compared with only 24.5 % (13/53) of reconstructions using jejunum. No difference in the frequency of postoperative adverse effects was seen between groups, but the frequency of diarrhea was significantly lower with reconstruction using jejunum.
Esophageal reconstruction using jejunum with the blood vessel processing technique results in both simpler and safer pulling up. Thus the need to perform supercharge and superdrainage is reduced.

DOI： 10.1007/s10388-014-0455-3

Enlarging lymphoepithelial cyst of the pancreas during 12 months of observation: report of a case

Daisuke Satoh, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara

SURGERY TODAY 45 ( 1 ) 101 - 104 2015.1

Language：English Publisher：SPRINGER

Pancreatic lymphoepithelial cysts (LECs) are rare benign pancreatic cystic lesions, the etiology of which is unknown. We report a case of a pancreatic LEC, discovered incidentally in a 63-year-old man during a follow-up clinic visit for an abdominal aneurysm. Computed tomography showed a multilocular cyst, 60-mm diameter in the body of the pancreas. This cyst increased from 6.0 to 6.5 cm during 12 months of observation. Part of the cyst was also visualized on positron emission tomography imaging. Since a pancreatic cystic neoplasm could not be ruled out, we performed distal pancreatectomy and postoperative pathological examination confirmed that the lesion was an LEC of the pancreas. Despite the conclusive postoperative findings, resection is unavoidable when a true pancreatic neoplasm cannot be excluded.

DOI： 10.1007/s00595-014-0960-y

A Case of Intra-Abdominal Desmoid Tumor Treated by Laparoscopic Surgery

Yagi Tomohiko, Inada Ryo, Nagasaka Takeshi, Watanabe Ayako, Matsumoto Hijiri, Toshima Toshiaki, Mori Yoshiko, Kondo Yoshitaka, Kishimoto Hiroyuki, Fujiwara Toshiyoshi

Nihon Gekakei Rengo Gakkaishi (Journal of Japanese College of Surgeons) 40 ( 1 ) 111 - 115 2015

Language：Japanese Publisher：Japanese College of Surgeons

A woman in her 60s had undergone partial nephrectomy for right renal cell carcinoma in 2009. Three years after that resection, a tumor measuring 40mm in diameter was identified near the ascending colon on follow-up computed tomography (CT), and she was referred to our department for management. Positron emission tomography (PET)-CT revealed both abnormal uptake of fluorodeoxyglucose by the tumor and absence of distant metastases. Colonoscopy showed a moderately elevated lesion like a submucosal tumor in the ascending colon. On suspicion of malignancy, laparoscopy-assisted right colectomy with lymphadenectomy was performed for diagnosis and treatment of the tumor. Histopathologically, the tumor was diagnosed as a desmoid tumor occurring in the mesentery of the ascending colon, and surgical margins were negative for tumor cells. The patient is doing well without recurrence as of 13 months postoperatively. We describe herein a relatively rare case of intra-abdominal desmoid tumor treated by laparoscopic surgery. Early surgical intervention should be considered for diagnosis and treatment.

DOI： 10.4030/jjcs.40.111

Other Link： http://search.jamas.or.jp/link/ui/2015308089

A Case of Primary Small Intestinal Adenocarcinoma with Difficult Preoperative Diagnosis

Matsumoto Hijiri, Inada Ryo, Kondo Yoshitaka, Watanabe Ayako, Yagi Tomohiko, Toshima Toshiaki, Mori Yoshiko, Kishimoto Hiroyuki, Nagasaka Takeshi, Fujiwara Toshiyoshi

Nihon Gekakei Rengo Gakkaishi (Journal of Japanese College of Surgeons) 40 ( 1 ) 61 - 65 2015

Language：Japanese Publisher：Japanese College of Surgeons

A 66-year-old man visited an initial hospital with a complaint of abdominal pain, and intra-abdominal abscess near the sigmoid colon was detected by abdominal CT scan. He got well by antibiotic medication. One year later, abdominal abscess recurred, and he was referred to our hospital for management. We performed capsule and double balloon endoscopy, indicating no malignant tumor at the small intestine. Intraoperatively small intestinal cancer with invasion to the rectum, metastases of lymph nodes and peritoneum was firstly diagnosed.Primary small intestinal adenocarcinoma is e a relatively rare disease with poor prognosis. Recently, capsule and double balloon endoscopy was reported to make contribution to get early diagnosis and improve prognosis. On the other hand, some cases remains to be difficult to make an early diagnosis like the case we described.

DOI： 10.4030/jjcs.40.61

Other Link： http://search.jamas.or.jp/link/ui/2015308079

遺伝子組換えアデノウイルスを用いたCirculating Tumor Cell検出系の開発と臨床応用

櫻井文教, 水口裕之, 藤原俊義

大和証券ヘルス財団研究業績集38号 108 - 112 2015

Multidisciplinary cancer therapy with telomerase-specific oncolytic adenovirus

Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

Current Cancer Therapy Reviews 11 ( 3 ) 178 - 187 2015

Language：English Publisher：Bentham Science Publishers B.V.

A multidisciplinary approach of combining surgery, chemotherapy and radiotherapy has remained the accepted standard management for various types of human cancer. However, many new treatment options have recently become available, including molecular targeted therapies, immunotherapies and oncolytic virotherapies. Replication-selective tu-mor-specific viruses have been designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. We constructed an attenuated adenovirus 5 vector, telomelysin (OBP-301), in which the telomerase-specific promoter drives expression of viral replication-inducible E1 genes. Although telomelysin alone exhibited substantial antitumor effects both in animal models and in clinical trials, telomelysin has the potential to be the first-in-class oncolytic virus for combination therapy based on our current understanding of the molecular mechanisms. Telomelysin sensitizes human cancer cells to ionizing radiation by inhibiting the radiation-induced DNA repair machinery, and also eliminates radio-resistant quiescent cancer stem-like cells by promoting cell cycle entry. A clinical trial of intratumoral administration of telomelysin with radiotherapy in esophageal cancer patients is currently underway. This article reviews recent highlights in the rapidly evolving field of multidisciplinary therapy with telomelysin.

DOI： 10.2174/1573394712666160128201822

Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

Takehara K, Tazawa H, Okada N, Hashimoto Y, Kikuchi S, Kuroda S, Kishimoto H, Shirakawa Y, Narii N, Mizuguchi H, Urata Y, Kagawa S, Fujiwara T

Mol Cancer Ther DOI: 10.1158/1535-7163 DOI: 10.1158/1535-7163 2015

Precise navigation surgery of tumours in the lung in mouse models enabled by in situ fluorescence labelling with a killer-reporter adenovirus

Shuya Yano, Yong Zhang, Shinji Miwa, Hiroyuki Kishimoto, Yasuo Urata, Michael Bouvet, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

BMJ Open Respiratory Research 2 ( 1 ) 1 - 6 2015

Language：English Publisher：BMJ Publishing Group

Background: Current methods of image-guided surgery of tumours of the lung mostly rely on CT. A sensitive procedure of selective tumour fluorescence labelling would allow simple and high-resolution visualisation of the tumour for precise surgical navigation. Methods: Human lung cancer cell lines H460 and A549 were genetically transformed to express red fluorescent protein (RFP). Tumours were grown subcutaneously for each cell line and harvested and minced for surgical orthotopic implantation on the left lung of nude mice. Tumour growth was measured by fluorescence imaging. After the tumours reached 5 mm in diameter, they were injected under fluorescence guidance with the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus, OBP-401. Viral labelling of the lung tumours with GFP precisely colocalised with tumour RFP expression. Three days after administration of OBP-401, fluorescence-guided surgery (FGS) was performed. Results: FGS of tumours in the lung was enabled by labelling with a telomerase-dependent adenovirus containing the GFP gene. Tumours in the lung were selectively and brightly labelled. FGS enabled complete lung tumour resection with no residual fluorescent tumour. Conclusions: FGS of tumours in the lung is feasible and more effective than bright-light surgery.

DOI： 10.1136/bmjresp-2015-000096

Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus

Yano S, Miwa S, Kishimoto H, Urata Y, Tazawa H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

J Orthop Res doi: 10.1002/jor.23073. [Epub ahead of print] 2015

Strategic approach to concurrent aberrant left gastric vein and aberrant left hepatic artery in laparoscopic distal gastrectomy for early gastric cancer: A case report

Kuwada K, Kuroda S, Kikuchi S, Hori N, Kubota T, Nishizaki M, Kagawa S, Fujiwara T

Asian J Endosc Surg 8 ( 4 ) 454 - 456 2015

6．血液凝固と線溶現象：b）血栓症の予防，診断および治療

黒田新士, 藤原俊義

外科 77 ( 12 ) 1385 - 1390 2015

Relative Prognostic and Predictive Value of Gene Signature and Histologic Grade in Estrogen Receptor–Positive, HER2-Negative Breast Cancer

Iwamoto T, Kelly C, Mizoo T, Nogami T, Motoki T, Shien T, Taira N, Hayashi N, Niikura N, Fujiwara T, Doihara H, Matsuoka J

Clin Breast Cancer doi: 10.1016/j.clbc.2015.10.004. 2015

Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study

Masako Terao, Akinobu Takaki, Takayuki Maruyama, Hiroki Oe, Tetsuya Yasunaka, Naofumi Tamaki, Kazufumi Nakamura, Takaaki Tomofuji, Takahito Yagi, Hiroshi Sadamori, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Kazuhiro Nouso, Daisuke Ekuni, Kazuko Koike, Fusao Ikeda, Hidenori Shiraha, Manabu Morita, Hiroshi Ito, Toshiyoshi Fujiwara, Kazuhide Yamamoto

INTERNAL MEDICINE 54 ( 22 ) 2815 - 2826 2015

Language：English Publisher：JAPAN SOC INTERNAL MEDICINE

Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH.
Methods We recruited patients with decompensated cirrhosis (n = 69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolararterial oxygen gradient (AaDO(2)) >= 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient >= 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study.
Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p = 0.037) and higher oxidative index values (p = 0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p = 0.049). The potential POPH patients exhibited elevated AaDO(2), suggesting the presence of pulmonary shunting.
Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

DOI： 10.2169/internalmedicine.54.4889

食道癌におけるFAP(fibroblast activation protein)陽性癌関連線維芽細胞の発現と癌転移の関係

賀島肇, 野間和広, 加藤卓也, 勝部亮一, 二宮卓之, 大原利章, 田澤大, 白川靖博, 香川俊輔, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 26th 2015

鉄制御を用いた新しい癌の浸潤・転移抑制治療法の開発

大原利章, 大原利章, 二宮卓之, 野間和広, 賀島肇, 加藤卓也, 勝部亮一, 白川靖博, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 26th 2015

癌関連線維芽細胞を標的とした新規食道癌治療法の開発

勝部亮一, 野間和広, 賀島肇, 加藤卓也, 二宮卓之, 大原利章, 田澤大, 白川靖博, 香川俊輔, 小林久隆, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 26th 2015

悪性腫瘍のウイルス療法:遺伝子改変ウイルス製剤の開発動向

藤原俊義

BIO INDUSTRY ( 32 ) 34 - 40 2015

ERASと周術期チーム医療

白川靖博, 加藤卓也, 竹原清人, 前田直見, 田辺俊介, 櫻間教文, 野間和広, 足羽孝子, 佐藤健治, 森松博史, 藤原俊義

臨床雑誌外科 77 ( 2 ) 142 - 146 2015

大腸癌早期発見のためのエピジェネティックバイオマーカーの開発

永坂岳司, 藤原俊義

G. I. Research 23 ( 1 ) 38 - 45 2015

Language：Japanese Publisher：(株)先端医学社

癌抑制遺伝子プロモーター領域のCpG island(CGI)に認められるメチル化異常は、当初、癌細胞だけに認められると考えられていたが、正常細胞にも頻度は少ないが認められることが報告されている。そのような癌特異的(と考えられた)DNAメチル化異常を大腸癌早期発見のためのエピジェネティックバイオマーカーに設定した場合、偽陽性率を上昇させることが示唆される。しかし、これらの現象は、注意深く検証していけば、大腸癌の進行度を推測する強力なマーカーに成りうる場合もある。本稿では、大腸癌スクリーニングの現状を概説し、便潜血反応検査(FOBT)を含めて、便から遺伝子変異を検出する方法の歴史的経過を概説したのちに、メチル化DNA検出による大腸癌スクリーニングの可能性について考察する。(著者抄録)

MicroRNA as a molecular target for gastrointestinal cancers

Tazawa H, Nagasaka T, Kagawa S, Fujiwara T

Transl Gastrointest Cancer 4 ( 3 ) 219 - 235 2015

消化器がん治療の最前線低侵襲治療と個別化医療

藤原俊義

山口県医学会誌 ( 49 ) 82 - 91 2015

放射線併用ウイルス療法による食道癌治療

藤原俊義

Isotope News ( 740 ) 2 - 6 2015

食道胃接合部手術に対する胸腔内観音開き法再建の検討

加藤卓也, 野間和広, 竹原清人, 前田直見, 田邊俊介, 櫻間教文, 西崎正彦, 香川俊輔, 白川靖博, 藤原俊義

日本消化器外科学会雑誌(Web) 48 ( Supplement1 ) 2015

消化器外科腹部領域のSSIに対する引き寄せと圧着を意識した局所陰圧閉鎖療法の実際

浪花崇一, 近藤喜太, 野間和広, 藤原俊義

日本創傷治癒学会プログラム・抄録集 45th 2015

Tumor-targeting Salmonella typhimurium A1-R decoys quiescent cancer cells to cycle as visualized by FUCCI imaging and become sensitive to chemotherapy

Shuya Yano, Yong Zhang, Ming Zhao, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 13 ( 24 ) 3958 - 3963 2014.12

Language：English Publisher：LANDES BIOSCIENCE

Quiescent cancer cells are resistant to cytotoxic agents which target only proliferating cancer cells. Time-lapse imaging demonstrated that tumor-targeting Salmonella typhimurium A1-R (A1-R) decoyed cancer cells in monolayer culture and in tumor spheres to cycle from G(0)/G(1) to S/G(2)/M, as demonstrated by fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging. A1-R infection of FUCCI-expressing subcutaneous tumors growing in nude mice also decoyed quiescent cancer cells, which were the majority of the cells in the tumors, to cycle from G(0)/G(1) to S/G(2)/M, thereby making them sensitive to cytotoxic agents. The combination of A1-R and cisplatinum or paclitaxel reduced tumor size compared with A1-R monotherapy or cisplatinum or paclitaxel alone. The results of this study demonstrate that A1-R can decoy quiescent cancer cells to cycle to S/G(2)/M and sensitize them to cytotoxic chemotherapy. These results suggest a new paradigm of bacterial-decoy chemotherapy of cancer.

DOI： 10.4161/15384101.2014.964115

Establishment of a Non-Invasive Semi-Quantitative Bioluminescent Imaging Method for Monitoring of an Orthotopic Esophageal Cancer Mouse Model

Shinji Kuroda, Tetsushi Kubota, Katsuyuki Aoyama, Satoru Kikuchi, Hiroshi Tazawa, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

PLOS ONE 9 ( 12 ) e114562 2014.12

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Orthotopic models of various types of tumors are widely used in anti-tumor therapeutic experiments in preclinical studies. However, there are few ways to appropriately monitor therapeutic effect in orthotopic tumor models, especially for tumors invisible from the outside. In this study we aimed to establish a non-invasive semi-quantitative bioluminescent imaging method of monitoring an orthotopic esophageal cancer mouse model. We confirmed that the TE8 esophageal cancer cell line implanted orthotopically into the abdominal esophagus of nu/nu mice (n=5) developed not only a main tumor at the implanted site, but also local lymph node metastases and peritoneal disseminations within 6 weeks after inoculation. We established a TE8 cell line that stably expressed the firefly luciferase gene (TE8-Luc). We showed that TE8-Luc cells implanted subcutaneously into nu/nu mice (n=5) grew over time until 5 weeks after inoculation. Tumor volume was strongly correlated with luminescent intensity emitted from the tumor, which was quantified using the IVIS imaging system. We then showed that TE8-Luc cells implanted orthotopically into the mouse abdominal esophagus (n=8) also formed a tumor and that the luminescent intensity of such a tumor, as detected by IVIS, increased over time until 7 weeks after inoculation and was therefore likely to reflect tumor progression. We therefore propose that this orthotopic esophageal cancer model, monitored using the non-invasive semi-quantitative IVIS imaging system, will be useful for in vivo therapeutic experiments against esophageal cancer. This experimental setting is expected to contribute to the development of novel therapeutic technologies for esophageal cancer in preclinical studies.

DOI： 10.1371/journal.pone.0114562

Molecular diagnosis and therapy for occult peritoneal metastasis in gastric cancer patients

Shunsuke Kagawa, Kunitoshi Shigeyasu, Michihiro Ishida, Megumi Watanabe, Hiroshi Tazawa, Takeshi Nagasaka, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

WORLD JOURNAL OF GASTROENTEROLOGY 20 ( 47 ) 17796 - 17803 2014.12

Language：English Publishing type：Book review, literature introduction, etc. Publisher：BAISHIDENG PUBLISHING GROUP INC

To apply an individualized oncological approach to gastric cancer patients, the accurate diagnosis of disease entities is required. Peritoneal metastasis is the most frequent mode of metastasis in gastric cancer, and the tumor-node-metastasis classification includes cytological detection of intraperitoneal cancer cells as part of the staging process, denoting metastatic disease. The accuracy of cytological diagnosis leaves room for improvement; therefore, highly sensitive molecular diagnostics, such as an enzyme immunoassay, reverse transcription polymerase chain reaction, and virus-guided imaging, have been developed to detect minute cancer cells in the peritoneal cavity. Molecular targeting therapy has also been spun off from basic research in the past decade. Although conventional cytology is still the mainstay, novel approaches could serve as practical complementary diagnostics to cytology in near future. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i47.17796

Risk Factors of Morbidity and Predictors of Long-term Survival after Hepatopancreatoduodenectomy for Biliary Cancer

Masashi Utsumi, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Kosei Takagi, Toshiyoshi Fujiwara, Takahito Yagi

HEPATO-GASTROENTEROLOGY 61 ( 136 ) 2167 - 2172 2014.11

Language：English Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: Hepatopancreatoduodenectomy (HPD) is performed to achieve radical resection of malignant biliary tumors. We reviewed clinical outcomes to evaluate the utility of HPD in terms of morbidity and mortality. Methodology: A retrospective analysis was conducted on 17 patients underwent HPD between August 1991 and May 2013; 9 bile duct cancel; 5 advanced gallbladder and 3pancreatic tumor with liver metastasis. Results: The morbidity and mortality rates were 88.3% and 0%, respectively. Univariate analysis showed that a body mass index of >= 22 and preoperative total bilirubin level >= 0.8 mg/dl were significantly associated with severe complications. One, 3- and 5-year survival rate were 73.3%, 60.0% and 30.0%. In 14 patients with biliary carcinoma, univariate analysis showed that a histological grade of G1 was significantly associated with survival. Patients without pancreatic invasion or portal vein invasion tended to survive longer than patients with these types of invasion, although the difference was not significant. Conclusions: HPD can be performed with no mortality and provides a survival benefit for some patients with biliary carcinoma undergoing curative resection. In patients with grade G1 biliary carcinoma without pancreatic or portal vein invasion in particular, this aggressive surgery might offer a chance of long-term survival.

DOI： 10.5754/hge14701

Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation

Ryuichiro Tsuzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Kazuko Koike, Yoshiaki Iwasaki, Hidenori Shiraha, Yasuhiro Miyake, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Eiichi Nakayama, Toshiyoshi Fujiwara, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 68 ( 5 ) 291 - 302 2014.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-gamma) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At > 3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.

DOI： 10.18926/AMO/52898

Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case

Kunitoshi Shigeyasu, Kohji Tanakaya, Takeshi Nagasaka, Hideki Aoki, Toshiyoshi Fujiwara, Kokichi Sugano, Hideki Ishikawa, Teruhiko Yoshida, Yoshihiro Moriya, Yoichi Furukawa, Ajay Goel, Hitoshi Takeuchi

SURGERY TODAY 44 ( 10 ) 1975 - 1981 2014.10

Language：English Publisher：SPRINGER

Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.

DOI： 10.1007/s00595-013-0669-3

Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker

Megumi Watanabe, Shunsuke Kagawa, Michihiro Ishida, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells

Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Hiroshi Tazawa, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Combination strategy of endoscopic resection and telomerase-targeting oncolytic virus for eradicating lymph node metastasis of submucosal invasive colorectal cancer

Naoto Hori, Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Development of systemically-deliverable telomerase-specific oncolytic adenovirus

Katsuyuki Aoyama, Shinji Kuroda, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Selective methioninase-induced trap of cancer cells in S/G(2) phase visualized by FUCCI imaging confers chemosensitivity

Shuya Yano, Shukuan Li, Qinghong Han, Yuying Tan, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 5 ( 18 ) 8729 - 8736 2014.9

Language：English Publisher：IMPACT JOURNALS LLC

A major impediment to the response of tumors to chemotherapy is that the large majority of cancer cells within a tumor are quiescent in G(0)/G(1), where cancer cells are resistant to chemotherapy. To attempt to solve this problem of quiescent cells in a tumor, cancer cells were treated with recombinant methioninase (rMETase), which selectively traps cancer cells in S/G(2). The cell cycle phase of the cancer cells was visualized with the fluorescence ubiquitination cell cycle indicator (FUCCI). At the time of rMETase-induced S/G(2)-phase blockage, identified by the cancer cells' green fluorescence by FUCCI imaging, the cancer cells were administered S/G(2)-dependent chemotherapy drugs, which interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil. Treatment of cancer cells with drugs only, without rMETase-induced S/G(2) phase blockage, led to the majority of the cancer-cell population being blocked in G(0)/G(1) phase, identified by the cancer cells becoming red fluorescent in the FUCCI system. The G(0)/G(1) blocked cells were resistant to the chemotherapy. In contrast, trapping of cancer cells in S/G(2) phase by rMETase treatment followed by FUCCI-imaging-guided chemotherapy was highly effective in killing the cancer cells.

Intussusception due to rectal adenocarcinoma in a young adult: A case report

Ryo Inada, Takeshi Nagasaka, Toshiaki Toshima, Yoshiko Mori, Yoshitaka Kondo, Hiroyuki Kishimoto, Toshiyoshi Fujiwara

WORLD JOURNAL OF GASTROENTEROLOGY 20 ( 35 ) 12678 - 12681 2014.9

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

An intussusception due to colonic adenocarcinoma has sometimes been reported. However, to the best of our knowledge, reports of intussusception due to rectal adenocarcinoma are extremely rare. In this report, the case of a young man with rectal adenocarcinoma causing intussusception is described. A 24-year-old man visited a hospital complaining of abdominal pain, and an upper rectal cancer was diagnosed by colonoscopy. Computed tomography showed intussusception caused by a large tumor in the pelvis and absence of distant metastases. Locally advanced rectal cancer causing intussusception was diagnosed, and a low anterior resection was performed. Intraoperatively, repair of the invagination could not be accomplished easily; therefore, the repair was abandoned. Instead, the tumor was removed en bloc to avoid dissemination of the cancer. Histopathologically, the tumor was diagnosed as a poorly differentiated adenocarcinoma, pStage. A. The patient has no evidence of recurrence at 10 mo after the operation. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i35.12678

MafA Is Required for Postnatal Proliferation of Pancreatic beta-Cells

Koki Eto, Wataru Nishimura, Hisashi Oishi, Haruhide Udagawa, Miho Kawaguchi, Masaki Hiramoto, Toshiyoshi Fujiwara, Satoru Takahashi, Kazuki Yasuda

PLOS ONE 9 ( 8 ) e104184 2014.8

Language：English Publisher：PUBLIC LIBRARY SCIENCE

The postnatal proliferation and maturation of insulin-secreting pancreatic beta-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional beta-cells. Maturation of beta-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for beta-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or beta-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of beta-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of beta-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of beta-cells via prolactin signaling.

DOI： 10.1371/journal.pone.0104184

Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness

Shuya Yano, Yong Zhang, Shinji Miwa, Yasunori Tome, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 13 ( 13 ) 2110 - 2119 2014.7

Language：English Publisher：LANDES BIOSCIENCE

The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G(0)/G(1) and 70% in S/G(2)/M. In contrast, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Similarly, approximately 75% of cancer cells far from (>100 mu m) tumor blood vessels of an established tumor are in G(0)/G(1). Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G(2)/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.

DOI： 10.4161/cc.29156

MECHANISM OF RESISTANCE TO TRASTUZUMAB AND MOLECULAR SENSITIZATION VIA ADCC ACTIVATION BY EXOGENOUS EXPRESSION OF HER2 EXTRACELLULAR DOMAIN

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 16 ( 7-8 ) 277 - 278 2014.7

肝細胞癌治療における外科手術の位置づけ再発肝細胞癌の治療方針再肝切除の有効性とSalvage transplantationの可能性

藤智和, 楳田祐三, 貞森裕, 篠浦先, 吉田龍一, 信岡大輔, 内海方嗣, 杭瀬崇, 八木孝仁, 藤原俊義

日本消化器外科学会総会 69回 WS - 5 2014.7

MiCRORNA-7 INHIBITS THE STEM-LIKE PROPERTIES OF CD133(+) HUMAN GASTRIC CANCER CELLS

Teppei Onishi, Hiroshi Tazawa, Shuya Yano, Yuuri Hashimoto, Ryosuke Yoshida, Shunsuke Kagawa, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 16 ( 7-8 ) 266 - 266 2014.7

Frequency of regulatory T-cell and hepatitis C viral antigen-specific immune response in recurrent hepatitis C after liver transplantation

Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Hiroshi Sadamori, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Eiichi Nakayama, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

TRANSPLANT IMMUNOLOGY 31 ( 1 ) 33 - 41 2014.6

Language：English Publisher：ELSEVIER SCIENCE BV

Introduction: Regulatory T (Treg) and type 1 regulatory T (Tr1) cells facilitate hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT). However, their frequencies and effects on HCV-specific immune responses have not been well investigated.
Methods: We determined Treg and Tr1 frequencies in OLT patients with hepatitis C and assessed their associations with HCV-specific T cell responses. These patients comprised the following groups: an early post-transplantation group (n = 14); an OLT-chronic active hepatitis C group (n = 14) with active hepatitis C (alanine aminotransferase of > upper limit of normal/positive for HCV-RNA); an OLT-persistently normal alanine aminotransferase group (n = 12) without active hepatitis C (not interferon/positive for HCV-RNA); and an OLT-sustained viral response group (n = 6) with sustained viral responses using interferon treatment (negative for HCV-RNA). The frequencies of HCV-specific CD4+ T cells that secreted interferon-gamma were determined by enzyme-linked immunosorbent spot assay (except for the OLT early group).
Results: Treg and Tr1 frequencies were low during the early post-transplantation period. OLT patients with sustained viral responses had lower Treg frequencies than those with chronic hepatitis C, whereas Tr1 frequencies were significantly reduced in OLT patients with persistently normal alanine aminotransferase levels compared to those with chronic hepatitis C (p < 0.05). Treg frequencies positively correlated with HCV NS3 antigen-specific interferon-gamma responses, which corresponded to HCV clearance.
Conclusions: Increased Treg frequencies and reduced HCV-NS3 antigen-specific responses recovered after viral eradication in post-OLT chronic hepatitis C patients. Reduced Tr1 frequencies were associated with hepatitis activity control, which may facilitate controlling chronic hepatitis C in patients after OLT. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.trim.2014.05.006

手術手技食道癌手術における用手補助的腹腔鏡下胃管作成の工夫

白川靖博, 前田直見, 田辺俊介, 大原利章, 野間和広, 藤原俊義

手術 68 ( 7 ) 951 - 954 2014.6

腫瘍縮小にて膵頭十二指腸切除術を回避できた膵Solid-pseudopapillary neoplasmの1例

信岡大輔, 八木孝仁, 篠浦先, 高木弘誠, 杭瀬崇, 内海方嗣, 吉田龍一, 楳田祐三, 貞森裕, 藤原俊義

日本癌治療学会誌 49 ( 3 ) 2101 - 2101 2014.6

Establishment of a pancreatic stem cell line from fibroblast-derived induced pluripotent stem cells

Takashi Kuise, Hirofumi Noguchi, Hiroshi Tazawa, Takashi Kawai, Masaya Iwamuro, Issei Saitoh, Hitomi Usui Kataoka, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara

BIOMEDICAL ENGINEERING ONLINE 13 doi:10.1186/1475-925X-13-64 2014.5

Language：English Publisher：BIOMED CENTRAL LTD

Background: For cell therapies to treat diabetes, it is important to produce a sufficient number of pancreatic endocrine cells that function similarly to primary islets. Induced pluripotent stem (iPS) cells represent a potentially unlimited source of functional pancreatic endocrine cells. However, the use of iPS cells for laboratory studies and cell-based therapies is hampered by their high tumorigenic potential and limited ability to generate pure populations of differentiated cell types in vitro. The purpose of this study was to establish a pancreatic stem cell line from iPS cells derived from mouse fibroblasts.
Methods: Mouse iPS cells were induced to differentiate into insulin-producing cells by a multi-step differentiation protocol, which was conducted as described previously with minor modifications. Selection of the pancreatic stem cell was based on morphology and Pdx1 expression. The pancreatic potential of the pancreatic stem cells was evaluated using a reverse transcription PCR, real-time PCR, immunofluorescence, and a glucose challenge test. To assess potential tumorigenicity of the pancreatic stem cells, the cells were injected into the quadriceps femoris muscle of the left hindlimb of nude mice.
Results: The iPS-derived pancreatic stem cells expressed the transcription factor -Pdx1- a marker of pancreatic development, and continued to divide actively beyond passage 80. Endocrine cells derived from these pancreatic stem cells expressed insulin and pancreatic genes, and they released insulin in response to glucose stimulation. Mice injected with the pancreatic stem cells did not develop tumors, in contrast to mice injected with an equal number of iPS cells.
Conclusion: This strategy provides a new approach for generation of insulin-producing cells that is more efficient and safer than using iPS cells. We believe that this approach will help to develop a patient-specific cell transplantation therapy for diabetes in the near future.

DOI： 10.1186/1475-925X-13-64

Molecular surgery using a novel biological agent, OBP-301, for lymph node micrometastasis in human colorectal cancer.

Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

JOURNAL OF CLINICAL ONCOLOGY 32 ( 15 ) 2014.5

Assistant-Based Standardization of Prone Position Thoracoscopic Esophagectomy

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Ryoichi Katsube, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 68 ( 2 ) 111 - 117 2014.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Thoracoscopic esophagectomy in the prone position (TEPP) might enable solo-surgery in cases requiring resection of the esophagus and the surrounding lymph nodes due to the associated advantages of good exposure of the surgical field and ergonomic considerations for the surgeon. However, no one approach can be for all patients requiring extensive lymphadenectomy. We recently developed an assistant-based procedure to standardize exposure of the surgical field. Patients were divided into 1 of 2 groups: a pre-standardization group (n = 37) and a post-standardization group (n = 28). The thoracoscopic operative time was significantly shorter (p= 0.0037)) in the post-standardization group (n = 28; 267 +/- 31min) than in the pre-standardization group (n = 37; 301 +/- 53 min). Further, learning curve analysis using the moving average method showed stabilization of the thoracoscopic operative time after the standardization. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the 2 groups. There were also no significant differences in the complication rate. Assistant-based surgery and standardization of the procedure resulted in a well-exposed and safe surgical field. TEPP decreased the operative time, even in patients requiring extensive lymphadenectomy.

DOI： 10.18926/AMO/52407

術前DCF療法が著効した食道原発内分泌細胞癌の1切除例

前田直見, 白川靖博, 國府島健, 大原利章, 田邊俊輔, 野間和広, 櫻間教文, 藤原俊義

岡山医学会雑誌 126 ( 1 ) 39 - 43 2014.4

Language：Japanese Publisher：岡山医学会

66歳男。心窩部痛を主訴とした。上部消化管造影検査所見で胸部中部食道(Mt)左-前壁に70mm大の周堤隆起明瞭な2型病変が認められた。上部消化管内視鏡検査所見で切歯より25cm〜33cmの食道左-前壁に半周性の2型病変を認められた。同部位の生検を施行し、内分泌細胞癌(小細胞型)と診断された。造影CT検査所見およびPET/CT検査より、胸部食道内分泌細胞癌(小細胞型)cT3cN1cM0:cStage IIIと診断し、術前補助化学療法2コースの後、手術の方針とした。化学療法は、docetaxel、cisplatin、5-fluorouracilの三剤を併用した。手術は腹臥位胸腔鏡下食道亜全摘、用手補助的腹腔鏡下胃管作製、3領域リンパ節郭清、胸骨後経路再建、頸部吻合を施行した。組織所見にて潰瘍部では加療による影響と考えられる線維化とヘモジデリンの沈着を認め、Grade 3と判定した。

DOI： 10.4044/joma.126.39

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00175&link_issn=&doc_id=20140415220008&doc_link_id=10.4044%2Fjoma.126.39&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.126.39&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

OP-001-6 温阻血再灌流+肝切除モデルにおけるHMGB1制御による再灌流障害および肝再生への影響解析(OP-001 肝基礎-1,一般演題,第114回日本外科学会定期学術集会)

杉原正大, 貞森裕, 西堀正洋, 佐藤康晴, 田澤大, 吉田龍一, 楳田祐三, 篠浦先, 永坂岳司, 八木孝仁, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 313 - 313 2014.3

OP-141-6 遺伝子変異情報を用いた直腸癌局所再発症例に対する治療戦略の検討(OP-141 直腸局所再発,一般演題,第114回日本外科学会定期学術集会)

永坂岳司, 母里淑子, 楳田祐三, 稲田涼, 森川達也, 横道直佑, 久保田暢人, 吉田一博, 竹原裕子, 河合毅, 藤智和, 竹原清人, 杭瀬崇, 谷口文崇, 近藤喜太, 岸本浩行, 浅野博昭, 佃憲和, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 564 - 564 2014.3

OP-076-6 外科を志す研修医教育に対する多視点多層三次元解剖教材の活用(OP-076 教育-2,一般演題,第114回日本外科学会定期学術集会)

近藤喜太, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 450 - 450 2014.3

PD-9-3 ロボット支援下噴門側胃切除術後のロボットによる体腔内手縫い食道残胃吻合(PD-9 パネルディスカッション(9)食道癌・胃癌におけるロボット支援手術の有用性,第114回日本外科学会定期学術集会)

西崎正彦, 黒田新士, 岸本浩行, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 189 - 189 2014.3

OP-006-5 膵頭十二指腸切除後の完全膵外瘻に対する非手術的内瘻化(OP-006 膵合併症-1,一般演題,第114回日本外科学会定期学術集会)

信岡大輔, 八木孝仁, 高木弘誠, 田村周太, 谷口文崇, 内海方嗣, 吉田龍一, 楳田祐三, 篠浦先, 貞森裕, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 322 - 322 2014.3

PS-027-7 膵頭十二指腸切除症例における創部SSI危険因子の検討 : 術前胆道ドレナージの合併症(PS-027 周術期管理 SSI・感染症,ポスターセッション,第114回日本外科学会定期学術集会)

谷口文崇, 八木仁, 貞森裕孝, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 内海方嗣, 田村周太, 高木弘誠, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 629 - 629 2014.3

OP-104-4 生体肝移植患者におけるItraconazoleの真菌感染症予防効果の検討(OP-104 肝周術期管理,一般演題,第114回日本外科学会定期学術集会)

内海方嗣, 貞森裕, 高木弘誠, 信岡大輔, 吉田龍一, 楳田祐三, 篠浦先, 八木孝仁, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 499 - 499 2014.3

OP-036-7 食道癌周術期における外科医の負担軽減に対しチーム医療が果たした役割(OP-036 周術期管理術後合併症・その他,一般演題,第114回日本外科学会定期学術集会)

白川靖博, 二宮卓之, 前田直見, 大原利章, 田辺俊助, 櫻間教文, 野間和広, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 379 - 379 2014.3

YIA-3-3 大腸癌肺転移に対するCTガイド下経皮的ラジオ波焼灼の短期・長期成績の検討(YIA-3 若手優秀演題賞(3)「消化管」,第114回日本外科学会定期学術集会)

稲田涼, 永坂岳司, 松本聖, 母里淑子, 近藤喜太, 岸本浩行, 楳田祐三, 浅野博昭, 佃和憲, 横道直佑, 久保田暢人, 河合毅, 吉田一博, 竹原清人, 森川達也, 竹原裕子, 平木隆夫, 金澤右, 八木孝仁, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 309 - 309 2014.3

OP-048-7 テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌に対する低侵襲治療の開発(OP-048 大腸その他,一般演題,第114回日本外科学会定期学術集会)

菊地覚次, 岸本浩行, 田澤大, 西崎正彦, 香川俊輔, 浦田泰生, Hoffman Robert, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 401 - 401 2014.3

PS-059-3 HER2陽性進行再発胃癌に対するTrastuzumabの使用経験とその有効性について(PS-059 胃集学的治療-3,ポスターセッション,第114回日本外科学会定期学術集会)

黒田新士, 香川俊輔, 渡邊めぐみ, 堀直人, 石田道拡, 岸本浩行, 西崎正彦, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 692 - 692 2014.3

PS-052-4 がん関連線維芽細胞(Cancer Associated Fibroblasts)を標的とした新規癌治療法の開発(PS-052 食道基礎-2,ポスターセッション,第114回日本外科学会定期学術集会)

野間和広, 白川靖博, 二宮卓之, 勝部亮一, 前田直見, 田辺俊介, 大原利章, 田澤大, 香川俊輔, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 678 - 678 2014.3

PS-113-5 大腸癌におけるproenostic factorとしてのmiRNA(PS-113 大腸基礎-1,ポスターセッション,第114回日本外科学会定期学術集会)

久保田暢人, 永坂岳司, 母里淑子, 森川達也, 吉田一博, 横道直佑, 稲田涼, 竹原裕子, 竹原清人, 河合毅, 藤智和, 楳田祐三, 田澤大, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 801 - 801 2014.3

RS-2-10 術前診断に難渋した原発性小腸癌の1例(RS-2 研修医の発表セッション(2)大腸,第114回日本外科学会定期学術集会)

松本聖, 稲田涼, 近藤喜太, 母里淑子, 永坂岳司, 藤原俊義

日本外科学会雑誌 115 ( 2 ) 1039 - 1039 2014.3

First successful case of simultaneous liver and kidney transplantation for patients with chronic liver and renal failure in Japan

Takahito Yagi, Daisuke Nobuoka, Susumu Shinoura, Yuzo Umeda, Daisuke Sato, Ryuichi Yoshida, Masashi Utsumi, Tomokazu Fuji, Hiroshi Sadamori, Toshiyoshi Fujiwara

HEPATOLOGY RESEARCH 44 ( 3 ) 358 - 363 2014.3

Language：English Publisher：WILEY-BLACKWELL

Establishment of a preferential liver allocation rule for simultaneous liver and kidney transplantation (SLK) and revisions of laws regarding organ transplants from deceased donors have paved the way for SLK in Japan. Very few cases of SLK have been attempted in Japan, and no such recipients have survived for longer than 40 days. The present report describes a case of a 50-year-old woman who had undergone living donor liver transplantation at the age of 38 years for management of post-partum liver failure. After the first transplant surgery, she developed hepatic vein stenosis and severe hypersplenism requiring splenectomy. She was then initiated on hemodialysis (HD) due to the deterioration of renal function after insertion of a hepatic vein stent. She was listed as a candidate for SLK in 2011 because she required frequent plasma exchange for hepatic coma. When her Model for End-stage Liver Disease score reached 46, the new liver was donated 46 days after registration. The reduced trisegment liver and the kidney grafts were simultaneously transplanted under veno-venous bypass and intraoperative HD. The hepatic artery was reconstructed prior to portal reconstruction in order to shorten anhepatic time. Although she developed subcapsular bleeding caused by hepatic contusion on the next day, subsequent hemostasis was obtained by transcatheter embolization. Thereafter, her recovery was uneventful, except for mild rejection and renal tubular acidosis of the kidney graft. This case highlights the need to establish Japanese criteria for SLK.

DOI： 10.1111/hepr.12122

Invading cancer cells are predominantly in G(0)/G(1) resulting in chemoresistance demonstrated by real-time FUCCI imaging

Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Hiroyuki Kishimoto, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 13 ( 6 ) 953 - 960 2014.3

Language：English Publisher：LANDES BIOSCIENCE

Invasive cancer cells are a critical target in order to prevent metastasis. In the present report, we demonstrate real-time visualization of cell cycle kinetics of invading cancer cells in 3-dimensional (3D) Gelfoam (R) histoculture, which is in vivo-like. A fluorescence ubiquitination cell cycle indicator (FUCCI) whereby G(0)/G(1) cells express a red fluorescent protein and S/G(2)/M cells express a green fluorescent protein was used to determine the cell cycle position of invading and non-invading cells. With FUCCI 3D confocal imaging, we observed that cancer cells in G(0)/G(1) phase in Gelfoam (R) histoculture migrated more rapidly and further than cancer cells in S/G(2)/M phases. Cancer cells ceased migrating when they entered S/G(2)/M phases and restarted migrating after cell division when the cells re-entered G(0)/G(1). Migrating cancer cells also were resistant to cytotoxic chemotherapy, since they were preponderantly in G(0)/G(1), where cytotoxic chemotherapy is not effective. The results of the present report suggest that novel therapy targeting G(0)/G(1) cancer cells should be developed to prevent metastasis.

DOI： 10.4161/cc.27818

Management Of Peritoneal Effusion by Sealing with a Self-Assembling Nanofiber Polypeptide Following Pelvic Surgery

Yoshitaka Kondo, Takeshi Nagasaka, Satoru Kobayashi, Naoya Kobayashi, Toshiyoshi Fujiwara

HEPATO-GASTROENTEROLOGY 61 ( 130 ) 349 - 353 2014.3

Language：English Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: PuraMatrix is a synthetic material consisting of 16-amino acid peptides that self-assemble into nanofibers, previously used as a scaffold for functional cell cultures. We conducted a clinical study to determine the safety and sealing properties of PuraMatrix in post-operative lymphorrhea following pelvic surgery in humans. Methodology: A total of 20 patients who underwent rectal cancer resection were analyzed. The study group (n = 10) consisted of patients who received PuraMatrix, matched with a control group (n = 10) of patients operated on conventionally. Results: During the 2 to 3 month follow-up period, there were no abnormal findings or adverse events in any the patients who received PuraMatrix. We found that the patients who received PuraMatrix had significantly reduced post-operative drainage volumes compared with the patients in the control group. Conclusions: PuraMatrix is a safe and effective bio-compatible sealing material for the management of post-operative peritoneal effusion following pelvic surgery.

DOI： 10.5754/hge121000

First successful case of simultaneous liver and kidney transplantation for patients with chronic liver and renal failure in Japan

Takahito Yagi, Daisuke Nobuoka, Susumu Shinoura, Yuzo Umeda, Daisuke Sato, Ryuichi Yoshida, Masashi Utsumi, Tomokazu Fuji, Hiroshi Sadamori, Toshiyoshi Fujiwara

HEPATOLOGY RESEARCH 44 ( 3 ) 358 - 363 2014.3

Language：English Publisher：WILEY-BLACKWELL

Establishment of a preferential liver allocation rule for simultaneous liver and kidney transplantation (SLK) and revisions of laws regarding organ transplants from deceased donors have paved the way for SLK in Japan. Very few cases of SLK have been attempted in Japan, and no such recipients have survived for longer than 40 days. The present report describes a case of a 50-year-old woman who had undergone living donor liver transplantation at the age of 38 years for management of post-partum liver failure. After the first transplant surgery, she developed hepatic vein stenosis and severe hypersplenism requiring splenectomy. She was then initiated on hemodialysis (HD) due to the deterioration of renal function after insertion of a hepatic vein stent. She was listed as a candidate for SLK in 2011 because she required frequent plasma exchange for hepatic coma. When her Model for End-stage Liver Disease score reached 46, the new liver was donated 46 days after registration. The reduced trisegment liver and the kidney grafts were simultaneously transplanted under veno-venous bypass and intraoperative HD. The hepatic artery was reconstructed prior to portal reconstruction in order to shorten anhepatic time. Although she developed subcapsular bleeding caused by hepatic contusion on the next day, subsequent hemostasis was obtained by transcatheter embolization. Thereafter, her recovery was uneventful, except for mild rejection and renal tubular acidosis of the kidney graft. This case highlights the need to establish Japanese criteria for SLK.

DOI： 10.1111/hepr.12122

Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER-negative/progesterone receptor-positive breast cancers

Mitsuya Itoh, Takayuki Iwamoto, Junji Matsuoka, Tomohiro Nogami, Takayuki Motoki, Tadahiko Shien, Naruto Taira, Naoki Niikura, Naoki Hayashi, Shoichiro Ohtani, Kenji Higaki, Toshiyoshi Fujiwara, Hiroyoshi Doihara, W. Fraser Symmans, Lajos Pusztai

BREAST CANCER RESEARCH AND TREATMENT 143 ( 2 ) 403 - 409 2014.1

Language：English Publisher：SPRINGER

We examined estrogen receptor (ER) mRNA expression and molecular subtypes in stage I-III breast cancers that are progesterone receptor (PR) positive but ER and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization. The ER, PR, and HER2 status was determined by IHC as part of routine clinical assessment (N = 501). Gene expression profiling was done with the Affymetrix U133A gene chip. We compared expressions of ESR1 and MKI67 mRNA, distribution of molecular subtypes by the PAM50 classifier, the sensitivity to endocrine therapy index, and the DLDA30 chemotherapy response predictor signature among ER/PR-positive (n = 223), ER-positive/PR-negative (<Emphasis Type="ItalicUnderline">n = 73), ER-negative/PR-positive (n = 20), and triple-negative (n = 185) cancers. All patients received neoadjuvant chemotherapy with an anthracycline and taxane and had adjuvant endocrine therapy only if ER or PR > 10 % positive. ESR1 expression was high in 25 % of ER-negative/PR-positive, in 79 % of ER-positive/PR-negative, in 96 % of ER/PR-positive, and in 12 % of triple-negative cancers by IHC. The average MKI67 expression was significantly higher in the ER-negative/PR-positive and triple-negative cohorts. Among the ER-negative/PR-positive patients, 15 % were luminal A, 5 % were Luminal B, and 65 % were basal like. The relapse-free survival rate of ER-negative/PR-positive patients was equivalent to ER-positive cancers and better than the triple-negative cohort. Only 20-25 % of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers. In this rare subset of patients (i) a second RNA-based assessment may help identifying the minority of ESR1 mRNA-positive, luminal-type cancers and (ii) the safest clinical approach may be to consider both adjuvant endocrine and chemotherapy.

DOI： 10.1007/s10549-013-2763-z

腺様嚢胞癌細胞株に対するテロメラーゼ特異的腫瘍融解ウイルスと放射線照射併用による抗腫瘍効果の検討

佐藤大典, 栗原祐史, 加藤光佑, 近藤誠二, 代田達夫, 浦田泰生, 藤原俊義, 新谷悟

日本口腔科学会雑誌 63 ( 1 ) 94 - 94 2014.1

A case of primary hepatic solitary fibrous tumor with simultaneous intrahepatic metastasis and pancreatic metastasis

Takashi Kuise, Yuzo Umeda, Hiroshi Sadamori, Susumu Shinoura, Ryuichi Yoshida, Daisuke Sato, Daisuke Nobuoka, Masashi Utsumi, Takahito Yagi, Toshiyoshi Fujiwara

Japanese Journal of Gastroenterological Surgery 47 ( 4 ) 215 - 222 2014

Language：Japanese Publisher：Japanese Society of Gastroenterological Surgery

Solitary fibrous tumor (SFT) is a relatively rare tumor that develops mostly as an intrathoracic lesion related to the pleura. Hepatic malignant SFTs are rare. Here, we present a case of a 56-year-old man with a bulky tumor in the right hepatic lobe. The tumor was found incidentally by abdominal CT as part of an examination for hepatic dysfunction. The definitive diagnosis of SFT was established after liver biopsy, and the patient was referred to our hospital for surgical treatment. At the first visit, imaging studies revealed the primary focus of the malignancy as well as metastatic lesions in the hepatic S2 segment and pancreatic body. The treatment regimen was as follows: after antecedent TAE, primary hepatic and intrahepatic metastatic foci were first resected by extended resection of the two central areas. Nine months later, the pancreatic head tumor was enucleated and distal pancreatectomy was performed to remove metastatic foci including the new lesion on the pancreatic head. Postoperative adjunctive therapy was not administered, and the patient is currently alive without recurrence 22 months postoperatively. To the best of our knowledge, there have only been a few reports on primary hepatic malignant SFTs and this is the only SFT case involving pancreatic metastases reported thus far. This case indicates that total tumor resection allows patients with distant metastasis to achieve recurrence-free survival. Should recurrence occur, we would proactively consider the use of molecular-targeted drugs (approved in 2012), with re-resection in mind. © 2014 The Japanese Society of Gastroenterological Surgery.

DOI： 10.5833/jjgs.2013.0002

ロボット支援下噴門側胃切除術後のロボットによる体腔内手縫い吻合

西﨑正彦, 黒田新士, 岸本浩行, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

癌の臨床 60 ( 3 ) 311 - 317 2014

直腸癌術後尿管再発の１例

松本聖, 稲田涼, 近藤喜太, 母里淑子, 岸本浩行, 江原伸, 戸田博子, 柳井広之, 永坂岳司, 藤原俊義

癌の臨床 60 ( 5 ) 549 - 554 2014

Language：Japanese Publisher：(株)篠原出版新社

尿管再発は大腸癌において頻度の低い再発形式である。今回直腸癌術後に血尿を契機に発見された左尿管再発を経験したので報告する。患者は80代男性。2007年1月、上部直腸癌に対して低位前方切除術を施行。病理診断にて中分化管状腺癌(pT4aN0M0、pStage II)と診断。2011年9月、血尿を認め、膀胱および左尿管に腫瘍を指摘。膀胱腫瘍に対してはTUR-BTを、また尿管腫瘍に対しては左腎尿管摘出術を施行。組織診断では膀胱腫瘍は、原発性尿路上皮癌と診断。また尿管腫瘍は腸管由来の分化型腺癌を認め、直腸癌の尿管再発と診断。その後、膀胱癌の局所再発および直腸癌の肺・膀胱内再発をきたすも、2012年5月、癒着性イレウスによる嘔吐に伴う誤嚥性肺炎により永眠された。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2014&ichushi_jid=J00297&link_issn=&doc_id=20141203210011&doc_link_id=%2Fad7gnrsc%2F2014%2F006005%2F011%2F0549-0554%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fad7gnrsc%2F2014%2F006005%2F011%2F0549-0554%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

FDG-PET/CTで再発大腸癌を疑った腹腔内膿瘍の1切除例

母里淑子, 永坂岳司, 稲田涼, 渡邉彩子, 岸本浩行, 近藤喜太, 藤原俊義

癌と化学療法 41 ( 12 ) 1599 - 1601 2014

Language：Japanese Publisher：(株)癌と化学療法社

症例は65歳、男性。腸穿孔を伴う下行結腸癌術後、補助化学療法中にCT、FDG-PET/CT検査にて脾臓・横隔膜にFDGの集積を認め術後再発と診断し、手術を施行したところ、腫瘍再発でなく膿瘍であった。腹膜播種の画像による確定診断は困難であり、特に腸穿孔後は感染性の集積も鑑別する必要がある。臨床的に示唆に富んだ症例を経験したので、文献的考察を含め報告する。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00296&link_issn=&doc_id=20141217480050&doc_link_id=%2Fab8gtkrc%2F2014%2F004112%2F050%2F1599-1601%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2014%2F004112%2F050%2F1599-1601%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

術前補助化学療法によりpCRが得られた高度進行胃癌の1例

菊地覚次, 香川俊輔, 久保田哲史, 桒田和也, 黒田新士, 西﨑正彦, 田中健大, 藤原俊義

癌と化学療法 41 ( 12 ) 2282 - 2284 2014

化学療法後に切除しpCRを得たStageⅣ胃癌の２例

久保田哲史, 香川俊輔, 菊地覚次, 黒田新士, 西﨑正彦, 藤原俊義

癌と化学療法 41 ( 12 ) 2308 - 2310 2014

分葉膵に付着した消化管重複症

尾山貴徳, 野田卓男, 谷本光隆, 楳田祐三, 藤智和, 八木孝仁, 藤原俊義

小児外科 46 ( 12 ) 1269 - 1273 2014

A Case of Advanced Esophageal Cancer with Pulmonary Hypertention due to Atrial Septal Defect

FUJITA Toshihiko, OHARA Toshiaki, TANABE Shunsuke, NOMA Kazuhiro, SHIRAKAWA Yasuhiro, FUJIWARA Toshiyoshi

Nihon Rinsho Geka Gakkai Zasshi (Journal of Japan Surgical Association) 75 ( 2 ) 384 - 387 2014

Language：Japanese Publisher：Japan Surgical Association

A 62-year-old man was detected to have advanced esophageal cancer with pulmonary hypertension (PH) due to atrial septal defect (ASD). We planned to perform radical repair of ASD and neoadjuvant chemotherapy before esophagectomy. However, he went into shock with melena by using an anticoagulant before cardiac catheterization. Endoscopic examination showed hemorrhage from the esophageal tumor, which suggested that ASD repair should be preceded by esophagectomy to remove the hemorrhage source. After esophagectomy, circulatory dynamics was unstable. Pulmonary arterial pressure (PAP) temporarily exceeded arterial pressure (AP) with coughing on the second day after the operation. Strict management with infusion and administration of vasopressin led to stable circulatory dynamics. However, unstable dynamics seemed to recur and we decided to repair ASD. Amplatzer Septal Occluder was inserted with intra cardiac echocardiography (ICE) because trans-esophageal echocardiography could not be used. After amplazter insertion, he became in good condition and was transferred to POD another hospital on 20.

DOI： 10.3919/jjsa.75.384

Other Link： http://search.jamas.or.jp/link/ui/2014159787

Hepatopulmonary syndrome in Japanese liver cirrhosis patients

Hayami Okada, Akinobu Takaki, Takahito Yagi, Tetsuya Yasunaka, Tatsuhiro Gotoda, Hiroki Oe, Kazufumi Nakamura, Shuichi Sato, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utsumi, Daisuke Nobuoka, Yuko Yasuda, Fusao Ikeda, Yasuhiro Miyake, Hiroshi Ito, Toshiyoshi Fujiwara, Kazuhide Yamamoto

Acta Hepatologica Japonica 55 ( 3 ) 143 - 154 2014

Language：Japanese

Hepatopulmonary syndrome is characterized by hypoxemia induced by intrapulmonary vascular dilatations associated with hepatic diseases. We evaluated the frequency and case presentations revealed by general screening before liver transplantation. Sixty-one patients underwent arterial blood gas analysis in both upright and supine positions. Of these, 27 patients (44%) showed Pa0&lt
inf&gt
2&lt
/inf&gt
&lt
80 mmHg and AaD0&lt
inf&gt
2&lt
/inf&gt
&gt
15 mmHg, reflecting intrapulmonary shunting. Four patients exhibited Pa0&lt
inf&gt
2&lt
/inf&gt
&lt
70 mmHg and orthodeoxia, defined as a fall in Pa0&lt
inf&gt
2&lt
/inf&gt
&gt
5% or 4 mmHg in an upright position. Finally, two patients showed hepatopulmonary syndrome, with positive findings on perfusion lung scanning. Both patients with hepatopulmonary syndrome had liver cirrhosis type C with habitual alcohol drinking and smoking. Potential pulmonary shunt patients with Pa0&lt
inf&gt
2&lt
/inf&gt
&lt
80 mmHg and AaD0&lt
inf&gt
2&lt
/inf&gt
&gt
15 mmHg exhibited higher model for end-stage liver disease scores. Care should be taken regarding hepatopulmonary syndrome during liver cirrhosis management in Japanese patients. © 2014 The Japan Society of Hepatology.

DOI： 10.2957/kanzo.55.143

A patient with primary malignant melanoma of the esophagus who underwent esophagectomy

Maeda Naoaki, Shirakawa Yasuhiro, Koujima Takeshi, Ohara Toshiaki, Tanabe Shunsuke, Noma Kazuhiro, Sakurama Kazuhumi, Fujiwara Toshiyosi

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 126 ( 1 ) 45 - 48 2014

Language：Japanese Publisher：Okayama Medical Association

We report the case of a 61-old-man with a primary malignant melanoma of the esophagus, an extremely rare and highly aggressive malignancy. He presented with dysphagia, and we performed an upper gastrointestinal endoscopy that detected a tumor in the thoracic part of the esophagus. The biopsy showed malignant melanoma. PET/CT, endoscopy and an esophagogram showed that a 70-mm scaled type 2+1 tumor in the thoracic esophagus and no metastases. We diagnosed a cT3cN0cM0 cStage II tumor. We then performed a subtotal esophagectomy with two-field lymph node dissection and esophagogastrostomy via a retrosternal route. The pathological examination of the resected specimens confirmed that the type 2+1 tumor was PMME (pT2N0M0 pStage II). We administered six courses of postoperative adjuvant chemotherapy with dacarbazine, and the patient has had no recurrence for 17 months after the surgery.

DOI： 10.4044/joma.126.45

Other Link： http://ousar.lib.okayama-u.ac.jp/52323

Biological Ablation of Sentinel Lymph Node Metastasis in Submucosally Invaded Early Gastrointestinal Cancer

Kikuchi S, Kishimoto H, Tazawa H, Hashimoto Y, Kuroda S, Nishizaki M, Nagasaka T, Shirakawa Y, Kagawa S, Urata Y, Hoffman RM, Fujiwara T

Mol Ther doi: 10.1038/mt.2014.244 2014

縮小手術のコツとピットフォール① 噴門側胃切除術（観音開き法）

西﨑正彦, 黒田新士, 松村年久, 高嶌寛年, 加藤大, 菊池覚次, 桒田和也, 香川俊輔, 藤原俊義

臨床外科 69 ( 13 ) 1464 - 1471 2014

固形癌に対する除鉄誘導による血管新生阻害薬併用療法の確立

大原利章, 木村文昭, 浦野真一, 二宮卓之, 勝部亮一, 野間和広, 友野靖子, 藤原俊義, 松川昭博

日本鉄バイオサイエンス学会学術集会プログラム・抄録集 38th 2014

非侵襲的肺癌スクリーニング法の開発

永坂岳司, 母里淑子, 重安邦俊, 豊岡伸一, 藤原俊義

日本遺伝子診療学会大会プログラム・抄録集 21st 2014

ターナー症候群に合併した若年性大腸癌の一例

母里淑子, 永坂岳司, 重安邦俊, 豊岡伸一, 藤原俊義

日本遺伝子診療学会大会プログラム・抄録集 21st 2014

鏡視下手術及び多職種による周術期管理による80歳以上超高齢者食道癌症例に対する手術成績向上の取り組み

田邊俊介, 白川靖博, 国府島健, 前田直見, 大原利章, 野間和広, 櫻間教文, 藤原俊義

日本消化器外科学会雑誌(Web) 47 ( Supplement1 ) 2014

癌関連線維芽細胞を標的とした光線免疫療法の開発

野間和広, 勝部亮一, 浦野真一, 大原利章, 白川靖博, 藤原俊義

日本がん転移学会学術集会・総会プログラム抄録集 23rd 2014

噴門側胃切除後の逆流防止機構を伴った食道残胃吻合法

西崎正彦, 黒田新士, 菊地覚次, 久保田哲史, 香川俊輔, 藤原俊義

胃癌perspective 7 ( 1 ) 20 - 26 2014

消化器癌のMolecular Theranostics:分子イメージングと治療の融合

藤原俊義

G.I.Research 22 ( 1 ) 24 - 30 2014

ウイルスを用いたDDS：悪性腫瘍のウイルス療法

藤原俊義

医薬ジャーナル 50 ( 7 ) 117 - 122 2014

テロメラーゼ活性依存的腫瘍融解ウイルスによるがん治療

田澤大, 矢野修也, 香川俊輔, 白川靖博, 藤原俊義

腫瘍内科 13 ( 6 ) 817 - 823 2014

胸部食道癌周術期栄養管理の検討

前田直見, 白川靖博, 田邊俊介, 野間和広, 櫻間教文, 坂本八千代, 佐野優子, 野口絢子, 藤原俊義

静脈経腸栄養 29 ( 1 ) 2014

腹臥位胸腔鏡下食道切除術における助手の積極的手野展開とその定型化

白川靖博, 野間和広, 藤原俊義

Gastroenterological Endoscopy 56 ( Supplement 1 ) 2014

噴門側胃切除術における逆流防止弁形成食道残胃吻合法の工夫と問題点

西崎正彦, 黒田新士, 菊地覚次, 桑田和也, 前田直見, 田邊俊介, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

胃外科・術後障害研究会プログラム・抄録集 44th 2014

Direct observation diverticulectomy for Zenker's diverticulum carcinoma

Toshiaki Ohara, Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Ryouichi Katsube, Shunsuke Tanabe, Toshiyoshi Fujiwara

ESOPHAGUS 10 ( 4 ) 235 - 238 2013.12

Language：English Publisher：SPRINGER JAPAN KK

Zenker's diverticulum carcinoma is a rare disease. Recent technological endoscopic innovation has enabled the detection of early stage Zenker's diverticulum carcinoma. Here we report a case in which a 56-year-old woman was diagnosed with early stage Zenker's diverticulum carcinoma. Narrow band imaging (NBI) endoscopic examination was useful for diagnosis and identifying the borders of the carcinoma. A successful surgical treatment was performed using direct observation diverticulectomy. A minimally invasive cervical procedure was used, and the area of the carcinoma was confirmed intraoperatively with Lugol's solution.

DOI： 10.1007/s10388-013-0376-6

Which patients respond best to hepatitis B vaccination after a hepatitis B virus-related liver transplantation?

Akinobu Takaki, Takahito Yagi, Tetsuya Yasunaka, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Sato, Daisuke Nobuoka, Masashi Utsumi, Yuko Yasuda, Eiichi Nakayama, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Kazuhiro Nouso, Toshiyoshi Fujiwara, Kazuhide Yamamoto

Journal of Gastroenterology 48 ( 12 ) 1373 - 1383 2013.12

Language：English

Background: A combination of hepatitis B immunoglobulin and nucleos(t)ide analogues is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, frequent immunoglobulin treatment is expensive and inconvenient. This study investigated the efficacy of hepatitis B virus (HBV) vaccination in preventing the recurrence of hepatitis B after living donor OLT. Methods: Twenty-seven patients who had undergone living donor OLT participated in the study
five had acute HBV infected liver failure (ALF-OLT) and 22 had HBV related liver cirrhosis (LC-OLT). Hepatitis B surface antigen (HBsAg)-containing vaccine was administered to them for at least 1 year after transplantation and continued once monthly for up to 36 months post-OLT. Patients who had anti-HBs antibody titers above 100 mIU/mL for a minimum of 6 months without immunoglobulin administration were defined as good responders
the others were defined as poor responders. Interferon-γ enzyme-linked immunospot assays against HBs and HBc antigens were used to assay cellular immune responses. Results: All five of the ALF-OLT patients had good responses after a median of four (range 2.5-5) vaccinations. Nine of the 22 LC-OLT patients had good responses after a median of 19 (range 11.5-30) vaccinations. Among the LC-OLT group, those with livers donated by relatively higher-aged, marital and high-titer anti-HBs antibody donors were good responders. LC-OLT patients classed as good responders showed interferon-γ responses comparable to those of the ALF-OLT patients. Conclusions: The ALF-OLT and LC-OLT patients who received livers from relatively higher-aged, marital, high-titer anti-HBs antibody donors were the best candidates for HBV vaccine administration. Boosting donors before transplantation may facilitate later vaccine response of the recipients. © 2013 The Author(s).

DOI： 10.1007/s00535-013-0763-8

Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines

Daisuke Sato, Yuji Kurihara, Seiji Kondo, Tatsuo Shirota, Yasuo Urata, Toshiyoshi Fujiwara, Satoru Shintani

ONCOLOGY REPORTS 30 ( 6 ) 2659 - 2664 2013.12

Language：English Publisher：SPANDIDOS PUBL LTD

We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase-contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients.

DOI： 10.3892/or.2013.2738

Multicentred surgical site infection surveillance using partitioning analysis

Y. Fujiwara, T. Yamada, Y. Naomoto, T. Yamatsuji, Y. Shirakawa, S. Tanabe, K. Noma, T. Kimura, H. Aoki, H. Matsukawa, M. Kimura, Y. Nonaka, H. Sasaki, T. Onoda, Y. Otawa, M. Takaoka, T. Fukazawa, Y. Ohno, T. Fujiwara

JOURNAL OF HOSPITAL INFECTION 85 ( 4 ) 282 - 288 2013.12

Language：English Publisher：W B SAUNDERS CO LTD

Background: Surgical site infection (SSI) is an ongoing major public health problem throughout the world that increases healthcare costs. Utilizing a methodology that can help clinicians to continuously collect data about SSIs, analyse it and implement the feedback into routine hospital practice has been identified as a top national priority in Japan.
Aim: To conduct an intervention study through 'operations research' using partitioning at multiple facilities, and to reduce the incidence and consequences of SSI.
Methods: The Setouchi SSI Surveillance Group, which consists of seven institutes, started SSI surveillance in 2006. Until May of 2008, there were four surveillance periods (A-D). In all, 3089 patients underwent gastrointestinal surgery and were followed up for 30 days after their operations. Twenty-six factors that have been reported to be related to SSI were evaluated for all patients. The top three factors from each surveillance period were determined and then actual practice improvements were planned for each subsequent period.
Findings: The total SSI occurrence was 6.9% for period A, 6.3% for period B, 6.4% for period C and 3.9% for period D. Comparing periods A and D, there was a statistical significance in the decrease of SSI occurrence (P = 0.012).
Conclusion: Using the results and partitioning analysis of active SSI surveillance to contribute to action plans for improving clinical practice was effective in significantly reducing SSIs. (C) 2013 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jhin.2013.08.002

Advanced hepatocellular carcinoma with lymph node metastases showing epithelial to mesenchymal transition effectively treated with systemic chemotherapy: Report of a case. International journal

Hiroshi Sadamori, Takahito Yagi, Kunitoshi Shigeyasu, Yuzo Umeda, Masahiro Sugihara, Naosuke Yokomichi, Toshiaki Ohara, Naoshi Nishida, Takeshi Nagasaka, Ajay Goel, Toshiyoshi Fujiwara

Hepatology research : the official journal of the Japan Society of Hepatology 43 ( 12 ) 1368 - 73 2013.12

Language：English

We present a case in which combination chemotherapy was used to successfully treat hepatocellular carcinoma (HCC) with rapid progression of lymph node (LN) metastases after liver resection. In addition, epithelial to mesenchymal transition (EMT) markers were examined immunohistochemically. A 43-year-old man who had been diagnosed with HCC showed an enlarged LN near the hepatic artery proper. After extended left lobectomy with lymphadenectomy in the hepatoduodenal ligament, he experienced rapid progression of metastases to the para-aortic and mediastinal LN. Partial remission was achieved after induction and maintenance of combination chemotherapy using etoposide, carboplatin, epirubicin and 5-fluorouracil. As a consequence of this treatment, the patient survived 10 months. Immunohistochemical studies demonstrated that HCC cells in the metastatic LN showed low expression of E-cadherin and high expression of N-cadherin and vimentin, indicating EMT. Combination chemotherapy may prove effective for patients with HCC accompanied by LN metastases that show features of EMT.

DOI： 10.1111/hepr.12080

A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G(2)/M Phases

Shuya Yano, Hiroshi Tazawa, Yuuri Hashimoto, Yasuhiro Shirakawa, Shinji Kuroda, Masahiko Nishizaki, Hiroyuki Kishimoto, Futoshi Uno, Takeshi Nagasaka, Yasuo Urata, Shunsuke Kagawa, Robert M. Hoffman, Toshiyoshi Fujiwara

CLINICAL CANCER RESEARCH 19 ( 23 ) 6495 - 6505 2013.12

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem-like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem-like cells.
Experimental Design: We established CD133(+) cancer stem-like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem-like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem-like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI).
Results: CD133(+) gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133(+) cancer stem-like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G(0)-G(1) to S/G(2)/M phases and subsequent cell death in quiescent CD133(+) cancer stem-like cells by mobilizing cell-cycle-related proteins. FUCCI enabled visualization of quiescent CD133(+) cancer stem-like cells and proliferating CD133(-) non-cancer stem-like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133(+) cancer stem-like cells maintained stemness by remaining in G(0)-G(1) phase. We showed that OBP-301 mobilized quiescent cancer stem-like cells in tumor spheres and xenografts into S/G(2)/M phases where they lost viability and cancer stem-like cell properties and became chemosensitive.
Conclusion: Oncolytic adenoviralinfection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem-like cells. Clin Cancer Res; 19(23); 6495-505. (C) 2013 AACR.

DOI： 10.1158/1078-0432.CCR-13-0742

Oncolytic Adenovirus-Induced Autophagy: Tumor-Suppressive Effect and Molecular Basis

Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 67 ( 6 ) 333 - 342 2013.12

Language：English Publishing type：Book review, literature introduction, etc. Publisher：OKAYAMA UNIV MED SCHOOL

Autophagy is a catabolic process that produces energy through lysosomal degradation of intracellular organelles. Autophagy functions as a cytoprotective factor under physiological conditions such as nutrient deprivation, hypoxia, and interruption of growth factors. On the other hand, infection with pathogenic viruses and bacteria also induces autophagy in infected cells. Oncolytic virotherapy with replication-competent viruses is thus a promising strategy to induce tumor-specific cell death. Oncolytic adenoviruses induce autophagy and subsequently contribute to cell death rather than cell survival in tumor cells. We previously developed a telomerase-specific replication-competent oncolytic adenovirus, OBP-301, which induces cell lysis in tumor cells with telomerase activities. OBP-301-mediated cytopathic activity is significantly associated with induction of autophagy biomarkers. In this review, we focus on the tumor-suppressive role and molecular basis of autophagic machinery induced by oncolytic adenoviruses. Addition of tumor-specific promoters and modification of the fiber knob of adenoviruses supports the oncolytic adenovirus-mediated autophagic cell death. Autophagy is cooperatively regulated by the El-dependent activation pathway, E4-dependent inhibitory pathway, and microRNA-dependent fine-tuning. Thus, future exploration of the functional role and molecular mechanisms underlying oncolytic adenovirus-induced autophagy would provide novel insights and improve the therapeutic potential of oncolytic adenoviruses.

DOI： 10.18926/AMO/52006

Quantitative assessment of Pdx1 promoter activity in vivo using a secreted luciferase reporter system

Wataru Nishimura, Koki Eto, Atsushi Miki, Motohito Goto, Miho Kawaguchi, Takao Nammo, Haruhide Udagawa, Masaki Hiramoto, Yukiko Shimizu, Tadashi Okamura, Toshiyoshi Fujiwara, Yoshikazu Yasuda, Kazuki Yasuda

Endocrinology 154 ( 11 ) 4388 - 4395 2013.11

Language：English

The luciferase reporter system is useful for the assessment of various biological processes in vivo. The transcription factor pancreatic and duodenal homeobox 1 (Pdx1) is critical for the formation and the function of pancreatic β-cells. A novel reporter system using secreted Gaussia princeps luciferase (GLuc) under the control of a Pdx1 promoter was generated and activated in rat and mouse β-cell lines. This Pdx1-GLuc construct was used as a transgene for the generation of reporter mice to monitor Pdx1 promoter activity in vivo via the measurement of secreted GLuc activity in a small aliquot of blood. Significantly increased plasma GLuc activity was observed in Pdx1-GLuc mice. Analysis of Pdx1-GLuc mice by bioluminescence imaging, GLuc reporter assays using homogenatesof various organs,andimmunohistochemistryrevealed thatGLucexpressionandactivity were exponentially higher in pancreatic β-cells than in pancreatic non-β-cells, the duodenum, and other organs. In addition, GLuc activity secreted into the culture medium from islets isolated from Pdx1-GLucmicecorrelatedwiththenumberofislets. ThetransplantationofPdx1-GLucisletsintosevere combined immunodeficiency mice elevated their plasma GLuc activity. Conversely, a partial pancreatectomy in Pdx1-GLuc mice reduced plasma GLuc activity. These results suggest that a secreted luciferase reporter system in vivo enables not only the monitoring of promoter activity but also a quantitative and minimally invasive assessment of physiological and pathological changes in small cell masses, such as pancreatic β-cells. Copyright © 2013 by The Endocrine Society.

DOI： 10.1210/en.2012-2248

Development of a Clinically-Precise Mouse Model of Rectal Cancer

Hiroyuki Kishimoto, Masashi Momiyama, Ryoichi Aki, Hiroaki Kimura, Atsushi Suetsugu, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

PLOS ONE 8 ( 11 ) 2013.11

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Currently-used rodent tumor models, including transgenic tumor models, or subcutaneously growing tumors in mice, do not sufficiently represent clinical cancer. We report here development of methods to obtain a highly clinically-accurate rectal cancer model. This model was established by intrarectal transplantation of mouse rectal cancer cells, stably expressing green fluorescent protein (GFP), followed by disrupting the epithelial cell layer of the rectal mucosa by instilling an acetic acid solution. Early-stage tumor was detected in the rectal mucosa by 6 days after transplantation. The tumor then became invasive into the submucosal tissue. The tumor incidence was 100% and mean volume (+/-SD) was 1232.4 +/- 994.7 mm(3) at 4 weeks after transplantation detected by fluorescence imaging. Spontaneous lymph node metastasis and lung metastasis were also found approximately 4 weeks after transplantation in over 90% of mice. This rectal tumor model precisely mimics the natural history of rectal cancer and can be used to study early tumor development, metastasis, and discovery and evaluation of novel therapeutics for this treatment-resistant disease.

DOI： 10.1371/journal.pone.0079453

Dynamic Color-Coded Fluorescence Imaging of the Cell-Cycle Phase, Mitosis, and Apoptosis Demonstrates How Caffeine Modulates Cisplatinum Efficacy

Shinji Miwa, Shuya Yano, Yasunori Tome, Naotoshi Sugimoto, Yukihiko Hiroshima, Fuminari Uehara, Sumiyuki Mii, Hiroaki Kimura, Katsuhiro Hayashi, Elena V. Efimova, Toshiyoshi Fujiwara, Hiroyuki Tsuchiya, Robert M. Hoffman

JOURNAL OF CELLULAR BIOCHEMISTRY 114 ( 11 ) 2454 - 2460 2013.11

Language：English Publisher：WILEY-BLACKWELL

Caffeine enhances the effect of certain anticancer drugs, but the mechanism of modulation is poorly understood. In this study, modulation of cisplatinum efficacy induced by caffeine was visualized at the subcellular level by real-time fluorescent-protein imaging. Mitotic and apoptotic changes were observed by imaging 143B human osteosarcoma dual-color cells, in which GFP is expressed in the nucleus and RFP is expressed in the cytoplasm. Modulation of the cell cycle was imaged using time-lapse imaging of HeLa cells expressing a fluorescent ubiquitination-based cell cycle indicator (FUCCI) in the nucleus. Clonogenic assays showed that caffeine increased the inhibition by cisplatinum on cell proliferation. Subcellular imaging demonstrated that cisplatinum decreased mitosis and induced apoptosis in 143B cells. The combination of cisplatinum and caffeine enhanced mitosis and subsequently increased apoptosis. Time-lapse imaging showed that cisplatinum strongly induced cell-cycle arrest in the S/G(2) phase in HeLa-FUCCI cells. Caffeine overcame the cell-cycle arrest induced by cisplatinum, thereby increasing its efficacy, since cisplatinum is ineffective against quiescent cells. The data in this report indicate that caffeine modulates the cell cycle in cancer cells, thereby enhancing efficacy of cell-cycle-dependent anticancer drugs such as cisplatinum. J. Cell. Biochem. 114: 2454-2460, 2013. (c) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.24593

Advances in adenovirus-mediated p53 cancer gene therapy

Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

Expert Opinion on Biological Therapy 13 ( 11 ) 1569 - 1583 2013.11

Language：English

Introduction: The tumor suppressor p53 gene regulates diverse cellular processes, such as cell-cycle arrest, senescence, apoptosis and autophagy, and it is frequently inactivated by genetic alterations in ∼ 50% of all types of human cancers. To restore wild-type p53 function in p53-inactivated tumors, adenovirus-mediated p53 gene therapy has been developed as a promising antitumor strategy in preclinical experiments and clinical studies. Areas covered: This review focuses on the clinical relevance of replication-deficient adenovirus vectors that carry the wild-type p53 gene (Ad-p53
Advexin, Gendicine and SCH-58500) in clinical studies of patients with various cancers and the future perspectives regarding conditionally replicating adenovirus vectors expressing the wild-type p53 gene (CRAd-p53
AdDelta24-p53, SG600-p53, OBP-702) in preclinical experiments. Moreover, the recent advances in our understanding of the molecular basis for the p53-mediated tumor suppression network induced by Ad-p53 and CRAd-p53 vectors and the combination therapies for promoting the therapeutic potential of adenovirus-mediated p53 gene therapy are discussed. Expert opinion: Exploration of the molecular mechanism underlying the p53-mediated tumor suppression network and the effective strategy for enhancing the p53-mediated cell death signaling pathway would provide novel insights into the improvement of clinical outcome in p53-based cancer gene therapy. © 2013 Informa UK, Ltd.

DOI： 10.1517/14712598.2013.845662

Serial Changes of Serum Growth Factor Levels and Liver Regeneration after Partial Hepatectomy in Healthy Humans

Kazuyuki Matsumoto, Yasuhiro Miyake, Yuzo Umeda, Hiroshi Matsushita, Hiroaki Matsuda, Akinobu Takaki, Hiroshi Sadamori, Kazuhiro Nouso, Takahito Yagi, Toshiyoshi Fujiwara, Kazuhide Yamamoto

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 14 ( 10 ) 20877 - 20889 2013.10

Language：English Publisher：MDPI AG

This study aimed to investigate the associations of the serial changes of serum levels of various growth factors with liver regeneration after hepatectomy in healthy liver donors. Sixteen healthy liver donors who underwent conventional liver resection were included. Serum levels of various growth factors before hepatectomy and on postoperative day (POD) 1, 3, 5 and 7 were measured. Liver volume data calculated by multi-detector computed tomography using workstation. The ratio of remnant liver volume on POD 0 to liver volume before the operation was 51% +/- 20%. The ratio of liver volume on POD 14 to liver volume on POD 0 were inversely correlated with remnant liver volume on POD 0 (r = -0.91). The ratio of liver volume on POD 14 to liver volume on POD 0 were significantly correlated with serum hepatocyte growth factor (HGF) levels on POD 1 (r = 0.54), serum leptin levels on POD 1 (r = 0.54), and serum macrophage colony-stimulating factor (M-CSF) levels on POD 5 (r = 0.76) and POD 7 (r = 0.80). These results suggest that early-phase elevation of serum levels of HGF, leptin and M-CSF may be associated with the acceleration of liver regeneration after hepatectomy in humans.

DOI： 10.3390/ijms141020877

Telomelysin shows potent antitumor activity through apoptotic and non-apoptotic cell death in soft tissue sarcoma cells

Gui-Dong Li, Hiroyuki Kawashima, Akira Ogose, Takashi Ariizumi, Tetsuo Hotta, Ryozo Kuwano, Yasuo Urata, Toshiyoshi Fujiwara, Naoto Endo

Cancer Science 104 ( 9 ) 1178 - 1188 2013.9

Language：English

This study investigated the pathway underlying the antitumor activity of telomelysin, a telomerase-dependent, replication-selective oncolytic adenovirus, in soft tissue sarcoma cells. Treatment with telomelysin alone resulted in simultaneous induction of apoptosis and autophagy, whereas cotreatment with telomelysin and 3-methyladenine significantly reduced cell viability and increased apoptosis and the cellular ATP level compared to treatment with telomelysin alone, indicating that telomelysin-mediated autophagy is a death-protective but not death-promoting process. Cotreatment with Z-Val-Ala-Asp-CH2F significantly increased cellular ATP depletion compared to telomelysin-alone treatment while inhibiting telomelysin-induced apoptosis and having no significant effect on cell viability, indicating that it promotes transition from apoptotic to necrotic cell death. © 2013 Japanese Cancer Association.

DOI： 10.1111/cas.12208

がんリスクの評価と予防便中メチル化CpG検出による消化器癌診断

永坂岳司, 吉田一博, 森川達也, 母里淑子, 横道直祐, 久保田暢人, 竹原祐子, 稲田涼, 楳田祐三, 西崎正彦, 香川俊輔, 西田直生志, 貞森裕, 八木孝仁, 藤原俊義

日本癌治療学会誌 48 ( 3 ) 590 - 590 2013.9

当院におけるパゾパニブの使用経験

元木崇之, 松岡順治, 岩本高行, 藤原俊義

日本癌治療学会誌 48 ( 3 ) 2079 - 2079 2013.9

Risk factors for acute renal injury in living donor liver transplantation: Evaluation of the RIFLE criteria

Masashi Utsumi, Yuzo Umeda, Hiroshi Sadamori, Takeshi Nagasaka, Akinobu Takaki, Hiroaki Matsuda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Daisuke Satoh, Tomokazu Fuji, Takahito Yagi, Toshiyoshi Fujiwara

Transplant International 26 ( 8 ) 842 - 852 2013.8

Language：English

Acute renal injury (ARI) is a serious complication after liver transplantation. This study investigated the usefulness of the RIFLE criteria in living donor liver transplantation (LDLT) and the prognostic impact of ARI after LDLT. We analyzed 200 consecutive adult LDLT patients, categorized as risk (R), injury (I), or failure (F), according to the RIFLE criteria. ARI occurred in 60.5% of patients: R-class, 23.5%
I-class, 21%
and F-class, 16%. Four patients in Group-A (normal renal function and R-class) and 26 patients in Group-B (severe ARI: I- and F-class) required renal replacement therapy (P &lt
0.001). Mild ARI did not affect postoperative prognosis regarding hospital mortality rate in Group A (3.2%), which was superior to that in Group B (15.8%
P = 0.0015). Fourteen patients in Group B developed chronic kidney disease (KDIGO stage 3/4). The 1-, 5- and 10-year survival rates were 96.7%, 90.6%, and 88.1% for Group A and 71.1%, 65.9%, and 59.3% for Group B, respectively (P &lt
0.0001). Multivariate analysis revealed risk factors for severe ARI as MELD ≥20 [odds ratio (OR) 2.9], small-for-size graft (GW/RBW &lt
0.7%
OR 3.1), blood loss/body weight &gt
55 ml/kg (OR 3.7), overexposure to calcineurin inhibitor (OR 2.5), and preoperative diabetes mellitus (OR 3.2). The RIFLE criteria offer a useful predictive tool after LDLT. Severe ARI, defined beyond class-I, could have negative prognostic impact in the acute and late postoperative phases. Perioperative treatment strategies should be designed and balanced based on the risk factors for the further improvement of transplant prognosis. © 2013 Steunstichting ESOT. Published by John Wiley &amp
Sons Ltd.

DOI： 10.1111/tri.12138

StageIII大腸癌根治術後の再発予測におけるMGMTプロモーター領域のメチル化解析の有用性

母里淑子, 永坂岳司, 竹原裕子, 吉田一博, 重安邦俊, 楳田祐三, 田澤大, 貞森裕, 藤原俊義

日本消化器外科学会総会 68回 O - 39 2013.7

温阻血再灌流+70%肝切除におけるHMGB1の動態解析と制御

杉原正大, 貞森裕, 佐藤太祐, 吉田龍一, 楳田祐三, 篠浦先, 田澤大, 永坂岳司, 八木孝仁, 藤原俊義

日本消化器外科学会総会 68回 RS - 54 2013.7

A novel synergistic effect of iron depletion on antiangiogenic cancer therapy

Toshiaki Ohara, Kazuhiro Noma, Shinichi Urano, Shinichiro Watanabe, Seishi Nishitani, Yasuko Tomono, Fumiaki Kimura, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 132 ( 11 ) 2705 - 2713 2013.6

Language：English Publisher：WILEY-BLACKWELL

Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion monotherapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The antitumor effects of iron depletion and antiangiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted antitumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.

DOI： 10.1002/ijc.27943

Peptide intra-tumor injection for cancer immunotherapy Enhancement of tumor cell antigenicity is a novel and attractive strategy

Daisuke Nobuoka, Toshiaki Yoshikawa, Toshiyoshi Fujiwara, Tetsuya Nakatsura

HUMAN VACCINES & IMMUNOTHERAPEUTICS 9 ( 6 ) 1234 - 1236 2013.6

Language：English Publisher：LANDES BIOSCIENCE

One of the problems in antigen-specific cancer immunotherapy is the low density of the tumor antigen-derived peptide endogenously presented on tumor cell surface major histocompatibility complex class I molecules. To overcome this, we are engaged in research on peptide intra-tumor injection to enhance tumor cell antigenicity. In in vivo studies using immunodeficient mice, the peptide injected into a solid mass of subcutaneous tumor was revealed to be loaded onto human leukocyte antigen class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, peptide intra-tumor injection was effective in terms of tumor growth inhibition and prolongation of survival time. Moreover, an antigen-spreading effect was detected after peptide intra-tumor injection. Peptide intra-tumor injection is an effective method of enhancing tumor cell antigenicity. It can induce additional peptide loading onto tumor cells, making tumor cells more antigenic for specific cytotoxic T-lymphocyte activity. Peptide intra-tumor injection may be a useful option for improvement of antigen-specific immunotherapy against solid tumors.

DOI： 10.4161/hv.23990

Appendicitis during pregnancy

75 ( 6 ) 622 - 625 2013.6

CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy

Daisuke Satoh, Takahito Yagi, Takeshi Nagasaka, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utsumi, Takehiro Tanaka, Hiroshi Sadamori, Toshiyoshi Fujiwara

World Journal of Hepatology 5 ( 4 ) 189 - 195 2013.4

Language：English

Aim: to investigate the pathogenesis of non-alcoholic fatty liver disease (nafld) after pancreatoduodenectomy (pd). methods: a cohort of 82 patients who underwent pd at okayama university hospital between 2003 and 2009 was enrolled and the clinicopathological features were compared between patients with and without nafld after pd. computed tomography (ct) images were evaluated every 6 mo after pd for follow-up. hepatic steatosis was diagnosed on ct when hepatic attenuation values were 40 hounsfield units. liver biopsy was performed for 4 of 30 patients with nafld after pd who consented to undergo biopsies. to compare nafld after pd with nafld associated with metabolic syndrome, liver samples were obtained from 10 patients with nafld associated with metabolic syndrome [fatty liver, n = 5
non-alcoholic steatohepatitis (nash), n = 5] by percutaneous ultrasonography-guided liver biopsy. double-fluorescence immunohistochemistry was applied to examine cd14 expression as a marker of lipopolysaccharide (lps)-sensitized macrophage cells (kupffer cells) in liver biopsy specimens. results: the incidence of postoperative nafld was 36.6% (30/82). univariate analysis identified cancer of the pancreatic head, sex, diameter of the main pancreatic duct, and dissection of the nerve plexus as factors associated with the development of nafld after pd. those patients who developed nafld after pd demonstrated significantly decreased levels of serum albumin, total protein, cholesterol and triglycerides compared to patients without nafld after pd, but no glucose intolerance or insulin resistance. liver biopsy was performed in four patients with nafld after pd. all four patients showed moderate-to-severe steatosis and nash was diagnosed in two. numbers of cells positive for cd68 (a marker of kupffer cells) and cd14 (a marker of lpssensitized kupffer cells) were counted in all biopsy specimens. the number of cd68+ cells in specimens of nafld after pd was significantly increased from that in specimens of nafld associated with metabolic syndrome specimens, which indicated the presence of significantly more kupffer cells in nafld after pd than in nafld associated with metabolic syndrome. similarly, more cd14+ cells, namely, lps-sensitized kupffer cells, were observed in nafld after pd than in nafld associated with metabolic syndrome. regarding nash, more cd68+ cells and cd14+ cells were observed in nash after pd specimens than in nash associated with metabolic syndrome. this showed that more kupffer cells and more lps-sensitized kupffer cells were present in nash after pd than in nash associated with metabolic syndrome. these observations suggest that after pd, kupffer cells and lps-sensitized kupffer cells were significantly upregulated, not only in nash, but also in simple fatty liver. conclusion: nafld after pd is characterized by both malnutrition and the up-regulation of cd14 on kupffer cells. gut-derived endotoxin appears central to the development of nafld after pd. © 2013 Baishideng.

DOI： 10.4254/wjh.v5.i4.189

Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination

Kunitoshi Shigeyasu, Shunsuke Kagawa, Futoshi Uno, Masahiko Nishizaki, Hiroyuki Kishimoto, Akira Gochi, Toshikazu Kimura, Takaomi Takahata, Yasuyuki Nonaka, Motoki Ninomiya, Toshiyoshi Fujiwara

Cancer Chemotherapy and Pharmacology 71 ( 4 ) 937 - 943 2013.4

Language：English

Purpose: Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination. Methods: Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m2/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m2 was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status. Results: Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1-43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %). Conclusions: Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination. © 2013 Springer-Verlag Berlin Heidelberg.

DOI： 10.1007/s00280-013-2086-0

Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy

Daisuke Nobuoka, Toshiaki Yoshikawa, Mari Takahashi, Tatsuaki Iwama, Kazutaka Horie, Manami Shimomura, Shiro Suzuki, Noriko Sakemura, Munehide Nakatsugawa, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara, Tetsuya Nakatsura

CANCER IMMUNOLOGY IMMUNOTHERAPY 62 ( 4 ) 639 - 652 2013.4

Language：English Publisher：SPRINGER

Antigen-specific cancer immunotherapy is a promising strategy for improving cancer treatment. Recently, many tumor-associated antigens and their epitopes recognized by cytotoxic T lymphocytes (CTLs) have been identified. However, the density of endogenously presented antigen-derived peptides on tumor cells is generally sparse, resulting in the inability of antigen-specific CTLs to work effectively. We hypothesize that increasing the density of an antigen-derived peptide would enhance antigen-specific cancer immunotherapy. Here, we demonstrated that intratumoral peptide injection leads to additional peptide loading onto major histocompatibility complex class I molecules of tumor cells, enhancing tumor cell recognition by antigen-specific CTLs. In in vitro studies, human leukocyte antigen (HLA)-A*02:01-restricted glypican-3(144-152) (FVGEFFTDV) and cytomegalovirus(495-503) (NLVPMVATV) peptide-specific CTLs showed strong activity against all peptide-pulsed cell lines, regardless of whether the tumor cells expressed the antigen. In in vivo studies using immunodeficient mice, glypican-3(144-152) and cytomegalovirus(495-503) peptides injected into a solid mass were loaded onto HLA class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, intratumoral injection of ovalbumin(257-264) peptide (SIINFEKL) was effective for tumor growth inhibition and survival against ovalbumin-negative tumors without adverse reactions. Moreover, we demonstrated an antigen-spreading effect that occurred after intratumoral peptide injection. Intratumoral peptide injection enhances tumor cell antigenicity and may be a useful option for improvement in antigen-specific cancer immunotherapy against solid tumors.

DOI： 10.1007/s00262-012-1366-6

Novel photoimmunotherapy (PIT) targeting cancer-associated fibroblasts (CAFs) for esophageal cancer.

Shinichiro Watanabe, Kazuhiro Noma, Shinichi Urano, Toshiaki Ohara, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 73 ( 8 ) 2013.4

PS-084-5 温阻血再灌流+肝切除モデルにおけるHMGBIの動態解析および肝再生機序の解明(PS ポスターセッション,第113回日本外科学会定期学術集会)

杉原正大, 貞森裕, 西堀正洋, 佐藤康晴, 田澤大, 吉田龍一, 楳田祐三, 篠浦先, 永坂岳司, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 637 - 637 2013.3

WS-12-1-2 当科における80歳以上の超高齢者食道癌症例に対する外科治療の変遷(WS ワークショップ,第113回日本外科学会定期学術集会)

田辺俊介, 白川靖博, 青山克幸, 前田直見, 大原利章, 櫻間教文, 野間和広, 西崎正彦, 香川俊輔, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 317 - 317 2013.3

SY-2-2 肝細胞癌に対する生体肝移植適応基準についての検討(SY シンポジウム,第113回日本外科学会定期学術集会)

佐藤太祐, 八木孝仁, 貞森裕, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 内海方嗣, 河合豪, 藤智和, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 108 - 108 2013.3

RSF-07-1 直腸癌術後10年を経過して発症した局所再発に対して治癒切除を施行した1例(RSF 研修医の発表セッション,第113回日本外科学会定期学術集会)

西江尚貴, 稲田涼, 近藤喜太, 宇野太, 永坂岳司, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 1071 - 1071 2013.3

PS-216-3 遺伝子変異情報を基盤とした大腸癌肝転移の治療戦略(PS ポスターセッション,第113回日本外科学会定期学術集会)

母里淑子, 楳田祐三, 永坂岳司, 稲田涼, 森川達也, 久保田暢人, 吉田一博, 篠浦先, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 822 - 822 2013.3

PS-105-4 難治性胆道狭窄・胆汁漏に対するランデブー法を用いた胆管内瘻化(PS ポスターセッション,第113回日本外科学会定期学術集会)

藤智和, 楳田祐三, 貞森裕, 河合毅, 内海方嗣, 信岡大輔, 佐藤太祐, 吉田龍一, 篠浦先, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 666 - 666 2013.3

PS-067-5 テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌の低侵襲治療の開発(PS ポスターセッション,第113回日本外科学会定期学術集会)

菊地覚次, 岸本浩行, 田澤大, 橋本悠里, 宇野太, 西崎正彦, 香川俊輔, 浦田泰生, Hoffman Robert, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 612 - 612 2013.3

PD-12-8 遺伝子情報を用いた多臓器転移大腸癌の検討および治療戦略の構築(PD パネルディスカッション,第113回日本外科学会定期学術集会)

稲田涼, 永坂岳司, 母里淑子, 楳田祐三, 森川達也, 久保田暢人, 近藤喜太, 宇野太, 貞森祐, 八木孝仁, 三嶋秀行, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 261 - 261 2013.3

VF-020-4 ロボット支援下幽門側胃切除術におけるリンパ節郭清手技(VF ビデオフォーラム,第113回日本外科学会定期学術集会)

西崎正彦, 香川俊輔, 石田道拡, 黒田新士, 近藤喜太, 野間和広, 岸本浩行, 宇野太, 永坂岳司, 白川靖博, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 438 - 438 2013.3

VSY-9-7 生体肝移植後に発生した肝・腎不全に対する脳死肝腎同時移植症例における術中リスクマネージ(VSY ビデオシンポジウム,第113回日本外科学会定期学術集会)

八木孝仁, 貞森裕, 楳田祐三, 篠浦先, 信岡大輔, 藤智和, 佐藤太柑, 内海方嗣, 吉田龍一, 河合毅, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 194 - 194 2013.3

VF-016-2 生体肝移植における人工血管を用いた血行再建(VF ビデオフォーラム,第113回日本外科学会定期学術集会)

信岡大輔, 楳田祐三, 貞森裕, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 保田裕子, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 434 - 434 2013.3

VF-079-4 下大静脈合併切除再建を併施した切除不能肝芽腫に対する生体肝移植(VF ビデオフォーラム,第113回日本外科学会定期学術集会)

吉田龍一, 藤智和, 河合毅, 内海方嗣, 信岡大輔, 佐藤大祐, 楳田祐三, 篠浦先, 貞森裕, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 495 - 495 2013.3

PD-3-6 生体肝移植の短期・晩期予後向上に向けた治療戦略個別化の可能性(PD パネルディスカッション,第113回日本外科学会定期学術集会)

楳田祐三, 八木孝仁, 貞森裕, 内海方嗣, 篠浦先, 吉田龍一, 佐藤太祐, 信岡大輔, 藤智和, 保田裕子, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 236 - 236 2013.3

PS-227-1 当院で治療を行った膵神経内分泌腫瘍35症例の画像所見と病理組織学的所見の検討(PS ポスターセッション,第113回日本外科学会定期学術集会)

内海方嗣, 藤智, 河合毅, 佐藤太祐, 信岡大輔, 吉田龍一, 楳田祐三, 篠浦先, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 837 - 837 2013.3

PS-082-3 血清鉄コントロールを用いた新たな肝細胞癌治療戦略(PS ポスターセッション,第113回日本外科学会定期学術集会)

大原利章, 白川靖博, 浦野真一, 前田直見, 渡邊伸一郎, 田辺俊介, 野間和広, 能祖一裕, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 634 - 634 2013.3

VF-018-3 生体肝移植ドナーにおける無血肝切除技術と胆道合併症の予防対策(VF ビデオフォーラム,第113回日本外科学会定期学術集会)

貞森裕, 八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 佐藤太祐, 信岡大輔, 内海方嗣, 杉原正大, 藤智和, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 436 - 436 2013.3

PS-089-4 サイトケラチン19発現は肝細胞癌の上皮間葉移行と肝外転移を予測する(PS ポスターセッション,第113回日本外科学会定期学術集会)

横道直佑, 永坂岳司, 西田直生志, 楳田祐三, 母里淑子, 森川達也, 久保田暢人, 吉田一博, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 644 - 644 2013.3

WS-17-7 テロメラーゼ活性を指標とする血中遊離癌細胞の高感度検出法の開発と遺伝子解析技術への応用(WS ワークショップ,第113回日本外科学会定期学術集会)

重安邦俊, 橋本悠里, 宇野太, 永坂岳司, 田澤大2), 香川俊輔, 水口裕之, 浦田泰生, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 338 - 338 2013.3

Telomerase-specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice

Wei-Hsiang Lin, Shiou-Hwei Yeh, Wan-Jen Yang, Kun-Huei Yeh, Toshiyoshi Fujiwara, Aisuke Nii, Stanley Shi-Chung Chang, Pei-Jer Chen

INTERNATIONAL JOURNAL OF CANCER 132 ( 6 ) 1451 - 1462 2013.3

Language：English Publisher：WILEY-BLACKWELL

The telomerase-specific replication-competent oncolytic adenovirus, Telomelysin, was developed for virus-mediated preferential lysis of tumor cells. Its selectivity is derived from a human telomerase reverse transcriptase (hTERT) promoter-driven active viral replication, which occurs in cancer cells with high telomerase activity but not in normal cells lacking such activity. Because the TERT activity is elevated in most cases of hepatocellular carcinoma (HCC), the current study aims to investigate whether Telomelysin can be used for treatment of HCC. The oncolytic effect of Telomelysin has been investigated both in vitro using cell culture and in vivo using an immunocompetent in situ orthotopic HCC model. In this model, HCC developed spontaneously in the liver of HBx transgenic mice, which is pathologically and genetically similar to human HCC. In cell culture assay, Telomelysin lyses HCC cell lines at a low multiplicity of infection (MOI), ranging 0.77-6.35 (MOI [PFU/cell]). In the orthotopic HCC model, Telomelysin showed a potent oncolytic effect on HCC but spared normal liver tissue. Dose escalation analysis identified a safety dose of 1.25 X 108 PFU for this model. The effect of multiple injections of Telomelysin was also evaluated in this immunocompetent HCC model. We found that the virus replicates in HCC after a second intratumoral injection despite an immune response induced by the previous injection. This preclinical study shows that Telomelysin can be used for treatment of human HCC at an appropriate dosage and that its tumor-killing activity persists after multiple injections.

DOI： 10.1002/ijc.27770

Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice. International journal

Toshio Nishikawa, Munenori Takaoka, Toshiaki Ohara, Yasuko Tomono, Huifang Hao, Xiaohong Bao, Takuya Fukazawa, Zhigang Wang, Kazufumi Sakurama, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

Cancer biology & therapy 14 ( 3 ) 230 - 6 2013.3

Language：English

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

DOI： 10.4161/cbt.23294

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

Joe Hasei, Tsuyoshi Sasaki, Hiroshi Tazawa, Shuhei Osaki, Yasuaki Yamakawa, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Teppei Onishi, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

MOLECULAR CANCER THERAPEUTICS 12 ( 3 ) 314 - 325 2013.3

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells. Mol Cancer Ther; 12(3); 314-25. (C)2012 AACR.

DOI： 10.1158/1535-7163.MCT-12-0869

下大静脈合併切除再建を併施した切除不能肝芽腫に対する生体肝移植

吉田龍一, 藤智和, 河合毅, 内海方嗣, 信岡大輔, 佐藤大祐, 楳田祐三, 篠浦先, 貞森裕, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 495 - 495 2013.3

当院で治療を行った膵神経内分泌腫瘍35症例の画像所見と病理組織学的所見の検討

内海方嗣, 藤智, 河合毅, 佐藤太祐, 信岡大輔, 吉田龍一, 楳田祐三, 篠浦先, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 837 - 837 2013.3

温阻血再灌流+肝切除モデルにおけるHMGB1の動態解析および肝再生機序の解明

杉原正大, 貞森裕, 西堀正洋, 佐藤康晴, 田澤大, 吉田龍一, 楳田祐三, 篠浦先, 永坂岳司, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 637 - 637 2013.3

同時性多臓器転移を有する大腸癌の治療戦略遺伝子情報を用いた多臓器転移大腸癌の検討および治療戦略の構築

稲田涼, 永坂岳司, 母里淑子, 楳田祐三, 森川達也, 久保田暢人, 近藤喜太, 宇野太, 貞森祐, 八木孝仁, 三嶋秀行, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 261 - 261 2013.3

In Vivo Imaging of Transplanted Islets Labeled with a Novel Cationic Nanoparticle

Koichi Oishi, Yoshitaka Miyamoto, Hiroaki Saito, Katsutoshi Murase, Kenji Ono, Makoto Sawada, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara, Shuji Hayashi, Hirofumi Noguchi

PLoS ONE 8 ( 2 ) 2013.2

Language：English

To monitor pancreatic islet transplantation efficiency, reliable noninvasive imaging methods, such as magnetic resonance imaging (MRI) are needed. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially-available magnetic nanoparticles are not efficiently transduced into cells. We herein report the in vivo detection of transplanted islets labeled with a novel cationic nanoparticle that allowed for noninvasive monitoring of islet grafts in diabetic mice in real time. The positively-charged nanoparticles were transduced into a β-cell line, MIN6 cells, and into isolated islets for 1 hr. MRI showed a marked decrease in the signal intensity on T1- and T2-weighted images at the implantation site of the labeled MIN 6 cells or islets in the left kidneys of mice. These data suggest that the novel positively-charged nanoparticle could be useful to detect and monitor islet engraftment, which would greatly aid in the clinical management of islet transplant patients. © 2013 Oishi et al.

DOI： 10.1371/journal.pone.0057046

Risk factors for organ/space surgical site infection after hepatectomy for hepatocellular carcinoma in 359 recent cases

Hiroshi Sadamori, Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Kazuhiro Yoshida, Toshiyoshi Fujiwara

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 20 ( 2 ) 186 - 196 2013.2

Language：English Publisher：SPRINGER JAPAN KK

Surgical site infections (SSIs), particularly organ/space SSIs, remain a common cause of major morbidity after hepatectomy for hepatocellular carcinoma (HCC).
Risk factors for SSIs were analyzed in 359 patients who underwent hepatectomy for HCC between 2001 and 2010. The causative bacteria, management, outcome, and characteristics of organ/space SSIs were investigated.
Anatomic hepatectomy was performed for 296 patients (82.5%), and repeat hepatectomy was carried out for 59 patients (16.4%). SSIs developed in 52 patients (14.5%; incisional, 24 cases; organ/space, 31 cases [3 patients showed both incisional and organ/space SSIs]). No in-hospital mortality related to incisional or organ/space SSIs was encountered. Independent risk factors for SSIs were repeat hepatectomy and operative time a parts per thousand yen280 min. Independent risk factors for organ/space SSIs were repeat hepatectomy and bile leakage. Methicillin-resistant Staphylococcus aureus was detected more frequently in organ/space SSIs after repeat hepatectomy than after initial hepatectomy.
Repeat hepatectomy and bile leakage represent independent risk factors for organ/space SSIs after hepatectomy for HCC. Establishing treatment strategies is important for preventing postoperative bile leakage and reducing the high rate of organ/space SSIs after repeat hepatectomy.

DOI： 10.1007/s00534-011-0503-5

Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability

Yuzo Umeda, Takeshi Nagasaka, Yoshiko Mori, Hiroshi Sadamori, Dong-Sheng Sun, Susumu Shinoura, Ryuich Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Kazuhiro Yoshida, Takahito Yagi, Toshiyoshi Fujiwara

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 20 ( 2 ) 223 - 233 2013.2

Language：English Publisher：SPRINGER JAPAN KK

The discovery of practical biomarkers is important to realize personalized medicine for patients with malignant neoplasias, including colorectal cancer (CRC).
The aim of this study was to determine reliable prognostic biomarkers by the analysis of patients with resectable colorectal liver metastases (CRLM).
Genomic DNA was obtained from the CRLM tissues of a cohort of 126 patients with CRLM with curative hepatic resection. The KRAS/BRAF mutation spectrum and microsatellite instability (MSI) status were successfully analyzed in 100 of the 126 CRLM tissues and these findings were examined in relation to the patients' clinical outcomes.
The cohort of 100 CRLM patients consisted of 46 with synchronous and 54 with metachronous liver metastasis. Overall survival and disease-free survival at 5 years were 57.4 and 24.9 %, respectively. MSI analysis revealed that none of the 100 CRLM specimens showed any evidence of MSI. By KRAS/BRAF mutation analysis, the analyzed CRLM patients were divided into 3 groups; KRAS-mutant (KRAS-Mt; n = 27), BRAF-mutant (BRAF-Mt; n = 3), and wild-types of both genes (Wild-type; n = 70). In the survival analysis, both KRAS-Mt and BRAF-Mt patients showed significantly poorer prognoses compared with Wild-type patients. Furthermore, although the population with the BRAF mutation was small, this mutation had a significant negative impact on disease-free survival.
In this study, all tumors in the cohort of CRLM patients were non-MSI tumors, suggesting MSI cancer in primary CRC would rarely reveal metastatic potential. KRAS and BRAF mutations are suggested to be poor prognostic factors in CRLM. Genetic information has an essential role as a prognostic marker and could contribute to the decisions on treatment strategy for CRLM.

DOI： 10.1007/s00534-012-0531-9

Bloodless Donor Hepatectomy in Living Donor Liver Transplantation: Counterclockwise Liver Rotation and Early Hanging Maneuver

Hiroshi Sadamori, Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Kazuhiro Yoshida, Toshiyoshi Fujiwara

JOURNAL OF GASTROINTESTINAL SURGERY 17 ( 1 ) 203 - 206 2013.1

Language：English Publisher：SPRINGER

Living donor hepatectomy is important because it determines donor safety and recipient outcome.
We applied the counter-clockwise liver rotation method and the hanging maneuver from an early stage in two major types of living donor operations.
Twenty-eight living donors underwent these procedures with significant reduction in blood loss. Right hepatectomy was performed in 14 of the donors and extended left hepatectomy was performed in the other 14 donors.
These techniques facilitate safe and bloodless living donor hepatectomy.

DOI： 10.1007/s11605-012-1907-5

A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus

T. Sasaki, H. Tazawa, J. Hasei, S. Osaki, T. Kunisada, A. Yoshida, Y. Hashimoto, S. Yano, R. Yoshida, S. Kagawa, F. Uno, Y. Urata, T. Ozaki, T. Fujiwara

GENE THERAPY 20 ( 1 ) 112 - 118 2013.1

Language：English Publisher：NATURE PUBLISHING GROUP

Adenovirus serotype 5 (Ad5) is frequently used as an effective vector for induction of therapeutic transgenes in cancer gene therapy or of tumor cell lysis in oncolytic virotherapy. Ad5 can infect target cells through binding with the coxsackie and adenovirus receptor (CAR). Thus, the infectious ability of Ad5-based vectors depends on the CAR expression level in target cells. There are conventional methods to evaluate the CAR expression level in human target cells, including flow cytometry, western blotting and immunohistochemistry. Here, we show a simple system for detection and assessment of functional CAR expression in human tumor cells, using the green fluorescent protein (GFP)-expressing telomerase-specific replication-competent adenovirus OBP-401. OBP-401 infection induced detectable GFP expression in CAR-expressing tumor cells, but not in CAR-negative tumor cells, nor in CAR-positive normal fibroblasts, 24 h after infection. OBP-401-mediated GFP expression was significantly associated with CAR expression in tumor cells. OBP-401 infection detected tumor cells with low CAR expression more efficiently than conventional methods. OBP-401 also distinguished CAR-positive tumor tissues from CAR-negative tumor and normal tissues in biopsy samples. These results suggest that GFP-expressing telomerase-specific replication-competent adenovirus is a very potent diagnostic tool for assessment of functional CAR expression in tumor cells for Ad5-based antitumor therapy. Gene Therapy (2013) 20, 112-118; doi:10.1038/gt.2011.213; published online 12 January 2012

DOI： 10.1038/gt.2011.213

Risk factors for major morbidity after liver resection for hepatocellular carcinoma

H. Sadamori, T. Yagi, S. Shinoura, Y. Umeda, R. Yoshida, D. Satoh, D. Nobuoka, M. Utsumi, T. Fujiwara

BRITISH JOURNAL OF SURGERY 100 ( 1 ) 122 - 129 2013.1

Language：English Publisher：WILEY-BLACKWELL

Background: Bile leakage, and organ and/or space surgical-site infection (SSI) are common causes of major morbidity after partial hepatectomy for hepatocellular carcinoma (HCC). The purpose of this study was to analyse risk factors for major morbidity and to explore strategies for its reduction after partial hepatectomy for HCC. Methods: Risk factors for bile leakage and organ/space SSI were analysed in patients who underwent partial hepatectomy for HCC between 2001 and 2010. The causes, management and outcomes of intractable bile leakage requiring endoscopic therapy or percutaneous transhepatic biliary drainage were analysed. In addition, causative bacteria, outcomes and characteristics of organ/space SSI were investigated. Risk factors were identified using multivariable analysis. Results: Some 359 patients were included in the analysis. The prevalence of bile leakage and organ/space SSI was 12.8 and 8.6 per cent respectively. Repeat hepatectomy and an operating time of at least 300 min were identified as independent risk factors for bile leakage. The main causes of intractable bile leakage were latent strictures of the biliary system caused by previous treatments for HCC and intraoperative injury of the hepatic duct during repeat hepatectomy. Independent risk factors for organ/space SSI were repeat hepatectomy and bile leakage. Methicillin-resistant Staphylococcus aureus was detected more frequently in organ/space SSI after repeat hepatectomy than after initial partial hepatectomy. Conclusion: Repeat hepatectomy and prolonged surgery were identified as risk factors for bile leakage after liver resection for HCC. Bile leakage and repeat hepatectomy increased the risk of organ/space SSI. Copyright (c) 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/bjs.8957

Antiproliferative effect of the HSP90 inhibitor NVP-AUY922 is determined by the expression of PTEN in esophageal cancer

Xiao-Hong Bao, Munenori Takaoka, Hui-Fang Hao, Takuya Fukazawa, Tomoki Yamatsuji, Kazufumi Sakurama, Nagio Takigawa, Motowo Nakajima, Toshiyoshi Fujiwara, Yoshio Naomoto

ONCOLOGY REPORTS 29 ( 1 ) 45 - 50 2013.1

Language：English Publisher：SPANDIDOS PUBL LTD

Heat shock protein 90 (HSP90), a molecular chaperone, has provoked great interest as a promising molecular target for cancer treatment, due to its involvement in regulating the conformation, stability and functions of key oncogenic proteins. At present, a variety of chemical compounds targeting HSP90 have been developed and have shown convincing anti-neoplastic activity in various preclinical tumor models. The aim of our study was to evaluate the antitumor effects of a novel HSP90 inhibitor, NVP-AUY922, in esophageal squamous cancer cells (ESCC). Four ESCC cell lines (TE-1, TE-4, TE-8, TE-10) were examined. NVP-AUY922 potently inhibited the proliferation of ESCC, particularly in PTEN-null TE-4 cells with a 2-3 times lower IC50 than the other three cell lines. Western blot analysis showed that PTEN-null TE-4 cells exhibited higher AKT and ERK activity, which contribute to cell proliferation and survival. NVP-AUY922 significantly suppressed the activity of AKT and ERK in TE-4 but not in PTEN-proficient TE-10 cells. Genetic modification experiments demonstrated that the sensitivity to NVP-AUY922 was decreased by exogenous transduction of PTEN in TE-4 and increased by silencing PTEN expression in intact PTEN-expressing TE-10, suggesting that the expression of PTEN may be associated with cell sensitivity in HSP90 inhibition. Furthermore, the enhanced activity of AKT in PTEN-silenced TE-10 was more easily suppressed by NVP-AUY922. Collectively, NVP-AUY922 exhibits a strong antiproliferative effect, revealing its potential as a novel therapeutic alternative to current ESCC treatment. The effect may be improved further by impeding PTEN expression.

DOI： 10.3892/or.2012.2074

Peptide vaccines for hepatocellular carcinoma

Daisuke Nobuoka, Toshiaki Yoshikawa, Yu Sawada, Toshiyoshi Fujiwara, Tetsuya Nakatsura

HUMAN VACCINES & IMMUNOTHERAPEUTICS 9 ( 1 ) 210 - 212 2013.1

Language：English Publisher：TAYLOR & FRANCIS INC

Immunotherapy is a potentially attractive treatment option for patients with hepatocellular carcinoma (HCC). We have reported that glypican-3 (GPC3) is an ideal target for anticancer immunotherapy against HCC because its expression is specifically detected in > 80% of HCCs, even during the early stages. Further, increased GPC3 expression is correlated with a poor prognosis. Based on results obtained from a preclinical study using mice, we conducted a phase I clinical trial using a GPC3-derived peptide vaccine. Phase I results showed that the GPC3-derived peptide vaccine was well tolerated. Furthermore, this was the first study to show that the frequency of peptide-specific cytotoxic T lymphocytes was correlated with overall survival in patients with HCC receiving a peptide vaccine. Next, we conducted a phase II clinical trial using the GPC3-derived peptide vaccine in patients with HCC after surgery or radiofrequency ablation (adjuvant setting). We are currently evaluating a third trial involving liver biopsies removed from patients with advanced HCC before and after GPC3-derived peptide vaccination. We expect that the results of these trials will result in future drug development.

DOI： 10.4161/hv.22473

Isolation Efficiency of Mouse Pancreatic Stem Cells Is Age Dependent

Kuise T, Noguchi H, Saitoh I, Kataoka H, Watanabe M, Noguchi Y, Fujiwara T

Cell Medicine 2013

遺伝子情報を用いた多臓器転移大腸癌の検討および治療戦略の構築.

稲田涼, 永坂岳司, 母里淑子, 楳田祐三, 森川達也, 久保田暢人, 竹原裕子, 河合毅, 宇野太, 八木孝仁, 藤原俊義

癌の臨床 2013

直腸癌術後10年を経て発症した局所再発に対して治癒切除を施行した1例.

西江尚貴, 稲田涼, 母里淑子, 近藤喜太, 宇野太, 永坂岳司, 藤原俊義

癌と化学療法 2013

A Case of Local Recurrence of Anal Canal Mucinous Adenocarcinoma at Five Years After an Initial Surgery

Hamada Yuki, Inada Ryo, Mori Yoshiko, Kondo Yoshitaka, Nagasaka Takeshi, Fujiwara Toshiyoshi

Nihon Gekakei Rengo Gakkaishi (Journal of Japanese College of Surgeons) 38 ( 5 ) 1086 - 1090 2013

Language：Japanese Publisher：Japanese College of Surgeons

A 61-year-old man underwent curative abdominoperineal resection with lateral lymph node dissection for anal canal mucinous adenocarcinoma at our hospital. Histopathological findings were pA, pN0, pH0, pP0, pM0, pStage Ⅱ, curA on the Japanese Classification of Colorectal Carcinoma, the seventh edition. Five years after the surgery, he complained of perineal pain and CT/MRI scans revealed a substantial recurrent tumor in the pelvis, measuring 90mm in diameter without other metastatic lesions. On the diagnosis of local recurrence of anal canal mucinous adenocarcinoma, we performed total pelvic exenteration (TPE), to eradicate the tumor in an en bloc fashion. He was discharged on the 25^th postoperative day without intra- and postoperative complications. Histopathologically, the specimens showed mucinous adenocarcinoma suggesting local recurrence of the primary tumor, and the radial margin was negative for cancer. The patient is doing well without any re-recurrence 28 months after TPE. Colorectal mucinous adenocarcinoma is a poor prognostic disease, compared with differentiated adenocarcinoma, and most of local recurrence arises within three years. We report a case of local recurrence of anal canal mucinous adenocarcinoma at five years after the initial surgery with good course and survival after TPE.

DOI： 10.4030/jjcs.38.1086

術後感染予防のための抗菌薬使用ガイドライン.

篠浦先, 藤原俊義

岡山医学会雑誌 2013

A case of metastatic cecal cancer with mutation in the BRAF oncogene and poor survival

125 ( 1 ) 47 - 50 2013

癌微小リンパ節転移を標的とするテロメラーゼ特異的制限増殖型ウイルス製剤の開発.

児島亨, 渡邉雄一, 橋本悠里, 黒田新士, 山崎泰源, 矢野修也, 田澤大, 宇野太, 香川俊輔, 田中紀章, 浦田泰生, 藤原俊義

岡山医学会雑誌 2013

New Surgical Approach to Large Splenorenal Shunt in Living Donor Liver Transplantation: Diversion of SMV and SPV Blood Flow

Hiroshi Sadamori, Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Toshiyoshi Fujiwara

Journal of Gastrointestinal Surgery 17 ( 2 ) 403 - 407 2013

Language：English

Introduction: The management of a large splenorenal shunt is important because it affects recipient outcome, particularly in living donor liver transplantation. Methods: To manage large splenorenal shunts in living donor liver transplantation, we diverted superior mesenteric vein and splenic portal vein blood flow by ligation at the root of the splenic portal vein. Result: This procedure was applied for five patients in whom superior mesenteric vein blood flow had been completely stolen by a splenorenal shunt preoperatively. Postoperative course was excellent in all cases. Conclusion: This technique completely prevents morbidity related to large splenorenal shunts after living donor liver transplantation. © 2012 The Society for Surgery of the Alimentary Tract.

DOI： 10.1007/s11605-012-2006-3

Kinetics of high-mobility group box 1 after living donor liver transplantation

Hiroshi Sadamori, Yasuharu Sato, Masahiro Nishibori, Daisuke Sato, Daisuke Nobuoka, Masahiro Sugihara, Takahito Yagi, Toshiyoshi Fujiwara

Japanese Journal of Gastroenterological Surgery 46 ( 3 ) 232 - 235 2013

The Maximum standardized uptake value is more reliable than size measurement in early follow-up to evaluate potential pulmonary malignancies following radiofrequency ablation.

Alafate A, Shinya T, Okumura Y, Sato S, Hiraki T, Ishii H, Gobara H, Kato K, Fujiwara T, Miyoshi S, Kaji M, Kanazawa S

Acta Med Okayama 2013

Successfully treated pneumatosis cystoides intestinalis with pneumoperitoneum onset in a patient administered α-glucosidase inhibitor.

Tanabe S, Shirakawa Y, Takehara Y, Maeda N, Katsube R, Ohara T, Sakurama K, Noma K, Fujiwara T

Acta Med Okayama 2013

Living donor liver transplantation to a survivor of liver resection for hepatocellular carcinoma with major portal vein invasion.

Sadamori H, Yagi T, Shinoura S, Umeda Y, Yoshida R, Sato D, Nobuoka D, Utsumi M, Fujiwara T

Acta Med Okayama 2013

進行食道癌における術前化学療法の現況.

田辺俊介, 白川靖博, 前田直見, 勝部亮一, 大原利章, 櫻間教文, 野間和広, 藤原俊義

癌と化学療法 2013

遠隔転帰・再発を伴う進行S状結腸癌に対して集学的治療を行い長期生存を得た1例.

西江尚貴, 稲田涼, 母里淑子, 近藤喜太, 宇野太, 永坂岳司, 内海方嗣, 楳田祐三, 貞森裕, 八木孝仁, 藤原俊義

癌と化学療法 2013

Genetically engineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis

125 ( 3 ) 195 - 199 2013

一次治療でセツキシマブ不耐となった後，三次治療での再使用により奏功した進行大腸癌の一例.

稲田涼, 永坂岳司, 母里淑子, 楳田祐三, 久保田暢人, 森川達也, 近藤喜太, 宇野太, 貞森裕, 八木孝仁, 藤原俊義

岡山医学会雑誌 2013

イマチニブが長期に奏効している同時性肝転移を伴う消化管間質腫瘍の１例.

宇野太, 藤原康宏, 藤原俊義

岡山医学会雑誌 2013

Occult Bleedingの検出により診断に至った, Hemosuccus Pancreaticusの1例.

杭瀬崇, 楳田祐三, 三村卓司, 金田道弘, 八木孝仁, 藤原俊義

胆と膵 2013

TWO CASES OF DIAPHRAGMATIC HERNIA FOLLOWING PERCUTANEOUS RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA

WATANABE Megumi, HAYASHI Dofu, MATSUMURA Toshihisa, NONAKA Yasuyuki, FUJIMARA Toshiyoshi

The journal of the Japanese Practical Surgeon Society 74 ( 8 ) 2128 - 2133 2013

Language：Japanese Publisher：Japan Surgical Association

Reports of diaphragmatic hernia associated with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) are rare. We report 2 cases of diaphragmatic hernia that developed after RFA for HCC. Case 1 involved a 65-year-old man who had undergone percutaneous RFA for HCC located in the S5 and S7 areas. Three years later, he underwent surgery from the abdominal cavity side based on the diagnosis of right diaphragmatic hernia made by another hospital. One year later, the right diaphragmatic hernia recurred, necessitating the performance of video-assisted thoracic surgery at our hospital. The defect of the diaphragm was covered with mesh. Case 2 involved a 73-year-old woman who had undergone percutaneous RFA for HCC located in the S7 area. Subsequently, she underwent 3 sessions of RFA for HCC localized in the S3, S1, and S4 areas. Seven years after the first RFA, right diaphragmatic hernia occurred, and we performed surgery via thoracotomy. The defect of the diaphragm was repaired by direct suture. The thoracotomic approach may be a safe and useful option for the treatment of diaphragmatic hernia after RFA.

DOI： 10.3919/jjsa.74.2128

Other Link： http://search.jamas.or.jp/link/ui/2014115098

A long-term control of gastrointestinal stromal tumor with sunitinib

Futoshi Uno, Yasuhiro Fujiwara, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 40 ( 9 ) 1241 - 1244 2013

Language：Japanese Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

The patient was a 70-year-old woman with gastrointestinal stromal tumor (GIST) of the small intestine, accompanied by liver metastasis. Multiple liver metastases were pointed out 3 months after R0 surgery (jejunectomy and hepatectomy). Although she was given radiofrequency ablation (RFA) therapy and imatinib, metastatic tumors progressed. In a further examination at our institution 21 months after R0 surgery, multiple liver, bone, and lung metastases were indicated, and she was given sunitinib once daily at a 50 mg in 6-week courses, with 4 weeks on and 2 weeks off treatment. Although sunitinib dosage was decreased to 25 mg/day because of adverse events, 21 courses of this treatment were administrered, and it took 137 weeks to progress her disease with this sunitinib treatment. At our institution, seven cases of GIST were treated with sunitinib, and the median time to progression was 30-weeks. That was almost the same result as for Japan and international clinical trials. Sunitinb treatment may be one of the most important therapeutic options for unresectable imatinib-resistant GIST.

下部直腸・肛門部疾患の診断と治療非上皮性悪性腫瘍.

稲田涼, 藤田伸, 谷口浩和, 宇野太, 永坂岳司, 藤原俊義

臨床消化器内科 2013

肝臓癌における除鉄併用ソラフェニブ療法の可能性

浦野真一, 大原利章, 勝部亮一, 友野靖子, 木村文昭, 野間和広, 白川靖博, 藤原俊義

日本鉄バイオサイエンス学会学術集会プログラム・抄録集 37th 2013

予後および病態評価が可能な新規食道癌同所移植性モデル

大原利章, 白川靖博, 野間和広, 浦野真一, 前田直見, 田辺俊介, 櫻間教文, 田澤大, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 24th 2013

遺伝子異常と癌の多様性癌遺伝子と癌抑制遺伝子の多様性と治療への応用.

藤原俊義

臨床と研究 90 ( 1 ) 38 - 42 2013

肝切除後の肝移植(生体及び脳死ドナー).

八木孝仁, 藤原俊義

手術 67 ( 7 ) 1071 - 1076 2013

消化器がんの分子病態に基づいた治療開発.

藤原俊義

第100回日本消化器病学会中国支部例会記念誌 181 - 187 2013

Molecular targeted therapies and gastroenterological neoplasia

125 ( 2 ) 145 - 152 2013

肺癌の遺伝子治療の現状．

藤原俊義

呼吸と循環 61 ( 6 ) 574 - 580 2013

次世代型制限増殖アデノウイルスを利用した血中循環がん細胞検出法の開発.

櫻井文教, 藤原俊義, 水口裕之

薬学雑誌 133 ( 3 ) 291 - 296 2013

80歳以上の超高齢者食道癌症例に対する外科治療の安全性確保への取り組み

田邊俊介, 白川靖博, 前田直見, 勝部亮一, 櫻間教文, 野間和広, 藤原俊義

日本消化器外科学会雑誌(Web) 46 ( Supplement1 ) 2013

同時性/異時性多発大腸癌における遺伝子変異の特徴

永坂岳司, 母里淑子, 豊岡伸一, 藤原俊義

日本人類遺伝学会大会プログラム・抄録集 58th 2013

Genetically engineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis

Hiroshi Tazawa, Shuya Yano, Ryosuke Yoshida, Yasumoto Yamasaki, Tsuyoshi Sasaki, Yuuri Hashimoto, Shinji Kuroda, Masaaki Ouchi, Teppei Onishi, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 131 ( 12 ) 2939 - 2950 2012.12

Language：English Publisher：WILEY-BLACKWELL

Autophagy is known to have a cytoprotective role under various cellular stresses; however, it also results in robust cell death as an important safeguard mechanism that protects the organism against invading pathogens and unwanted cancer cells. Autophagy is regulated by cell signalling including microRNA (miRNA), a post-transcriptional regulator of gene expression. Here, we show that genetically engineered telomerase-specific oncolytic adenovirus induced miR-7 expression, which is significantly associated with its cytopathic activity in human cancer cells. Virus-mediated miR-7 upregulation depended on enhanced expression of the E2F1 protein. Ectopic expression of miR-7 suppressed cell viability and induced autophagy by inhibiting epidermal growth factor receptor (EGFR) expression. Our results suggest that oncolytic adenovirus induces autophagic cell death through an E2F1-miR-7-EGFR pathway in human cancer cells, providing a novel insight into the molecular mechanism of an anticancer virotherapy.

DOI： 10.1002/ijc.27589

Jejunal interposition reconstruction with a stomach preserving esophagectomy improves postoperative weight loss and reflux symptoms for esophageal cancer patients

Eiji Yamada, Yasuhiro Shirakawa, Tomoki Yamatsuji, Leon Sakuma, Munenori Takaoka, Takako Yamada, Kazuhiro Noma, Kazufumi Sakurama, Yasuhiro Fujiwara, Shunsuke Tanabe, Takeshi Nagasaka, Toshiyoshi Fujiwara, Yoshio Naomoto

JOURNAL OF SURGICAL RESEARCH 178 ( 2 ) 700 - 707 2012.12

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Background: Conventional reconstruction after an esophagectomy uses a gastric tube, which commonly causes several postoperative complaints such as gastric acid reflux in long-term survival cases. Intestinal interposition between the remnant esophagus and the stomach is an option to reduce complaints, and in this study, the advantages of jejunal interposition reconstruction with a stomach preserving esophagectomy (SPE) were assessed.
Materials and methods: Eleven cases of jejunal interposition with an SPE and 16 cases with gastric tube reconstruction as a control were subject to a comparison of operation time, amount of bleeding, postoperative quality of life, and endoscopic findings.
Results: The SPE group had a longer operation time (SPE: 560 +/- 121 min, control 414 +/- 83 min, P = 0.038), whereas there was no significant difference in blood loss. Postoperative weight loss was significantly recovered in the SPE group (SPE versus control = 94.0 +/- 5.4% versus 87.5 +/- 4.7% at 3 mo, P = 0.017; 97.2 +/- 7.5% versus 85.0 +/- 5.2% at 6 mo, P = 0.010), and there was a significant decrease in the occurrence of reflux symptoms such as heartburn, odynophagia, and cough when jejunal interposition with an SPE was done. Furthermore, reflux esophagitis and Barrett's epithelium were found in six out of 12 cases (50%) of the control group by postoperative endoscopy, while no cases in the SPE group had either condition (P < 0.01).
Conclusions: This reconstruction method is a promising option to improve postoperative quality of life, mainly due to the long-term elimination of reflux esophagitis, which assists in the recovery of postoperative weight loss. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jss.2012.07.057

Surgical rationalization of living donor liver transplantation by abolition of hepatic artery reconstruction under a fixed microscope

Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Daisuke Sato, Ryuichi Yoshida, Kazuhiro Yoshida, Masashi Utsumi, Daisuke Nobuoka, Hiroshi Sadamori, Toshiyoshi Fujiwara

CLINICAL TRANSPLANTATION 26 ( 6 ) 877 - 883 2012.11

Language：English Publisher：WILEY-BLACKWELL

The small diameter of the hepatic artery is one of the complexities of living donor liver transplantation (LDLT). We analyzed whether the direct suture technique using surgical loupes can simplify the operative process for LDLT compared with fixed microscopic reconstruction. We applied the direct technique to rationalize the operative process and abolished routine microsurgery from 2004. Two hundred and nine LDLT with a postoperative period over 34 months were carried out from 1996 to 2008. The patients were divided into two groups: the micro group (children: 20, adults: 72) and the non-micro group (children: 12, adults: 97). Running anastomosis was undertaken in the non-micro group. The anastomotic size of the children was significantly smaller than that of the adults, but larger than 2 mm (2.38 +/- 0.4 vs. 2.7 +/- 0.47 mm, p = 0.0005). By appropriate choice of the proximal artery, direct anastomosis is possible even in children. Early complications occurred in seven cases in the micro group, but none occurred in the non-micro group (p < 0.05). Significant reductions were observed in operation time (p < 0.0001), blood loss (p < 0.05), and hospital stay (p < 0.01) in the non-micro group. Non-microscopic anastomosis is useful for the rationalization of LDLT.

DOI： 10.1111/j.1399-0012.2012.01651.x

Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells

Y. Watanabe, Y. Hashimoto, S. Kagawa, H. Kawamura, K. Nagai, N. Tanaka, Y. Urata, T. Fujiwara

CANCER GENE THERAPY 19 ( 11 ) 767 - 772 2012.11

Language：English Publisher：NATURE PUBLISHING GROUP

Replication-selective oncolytic viruses are being developed for human cancer therapy. We previously developed an attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site. OBP-301 can replicate in, and causes selective lysis of, human cancer cells. Valproic acid (VPA), which is an effective antiepileptic drug, is known to inhibit the histone deacetylase activities. We determined whether the antitumor effect of OBP-301 could be enhanced by VPA in human lung cancer cells. In an in vitro cell viability assay, OBP-301 infection killed four human lung cancer cell lines, H1299, H1299-R5 (a subline of H1299 with a low level of the coxsackievirus and adenovirus receptor (CAR) expression), H460, and A549, more efficiently in the presence of VPA than in its absence. VPA treatment increased CAR expression in all the four lung cancer cells. Consistent with their CAR upregulation, the infection efficiency of adenoviruses in the presence of VPA was significantly higher than that in its absence. The molecular mechanism of this combined effect could be explained by an increase in adenovirus infectivity via VPA-mediated upregulation of CAR. These results suggest that treatment with OBP-301 in combination with VPA is a promising strategy for human lung cancer.

DOI： 10.1038/cgt.2012.57

Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Shuya Yano, Teppei Onishi, Tsuyoshi Sasaki, Yasuhiro Shirakawa, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER IMMUNOLOGY IMMUNOTHERAPY 61 ( 11 ) 1905 - 1916 2012.11

Language：English Publisher：SPRINGER

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1007/s00262-012-1249-x

進行肝細胞癌の治療高度脈管浸潤を伴う進行肝細胞癌の治療戦略

藤智和, 楳田祐三, 貞森裕, 篠浦先, 吉田龍一, 佐藤太祐, 信岡大輔, 内海方嗣, 河合毅, 藤原俊義, 八木孝仁

日本臨床外科学会雑誌 73 ( 増刊 ) 409 - 409 2012.10

同時性肝内転移、膵転移を伴った肝原発solitary fibrous tumorの一例

杭瀬崇, 楳田祐三, 貞森裕, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 藤智和, 八木孝仁, 藤原俊義

日本臨床外科学会雑誌 73 ( 増刊 ) 696 - 696 2012.10

A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour-specific p53 overexpression through E1A-dependent p21 and MDM2 suppression

Yasumoto Yamasaki, Hiroshi Tazawa, Yuuri Hashimoto, Toru Kojima, Shinji Kuroda, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Hiroyuki Mizuguchi, Akira Ohtsuru, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

EUROPEAN JOURNAL OF CANCER 48 ( 14 ) 2282 - 2291 2012.9

Language：English Publisher：ELSEVIER SCI LTD

Oncolytic viruses engineered to replicate in tumour cells but not in normal cells could be used as tumour-specific vectors carrying the therapeutic genes. We previously developed a telomerase-specific oncolytic adenovirus, OBP-301, that causes cell death in human cancer cells with telomerase activities. Here, we further modified OBP-301 to express the wild-type p53 tumour suppressor gene (OBP-702), and investigated whether OBP-702 induces stronger antitumour activity than OBP-301. The antitumour effect of OBP-702 was compared to that of OBP-301 on OBP-301-sensitive (H358 and H460) and OBP-301-resistant (T.Tn and HSC4) human cancer cells. OBP-702 suppressed the viability of both OBP-301-sensitive and OBP-301-resistant cancer cells more efficiently than OBP-301. OBP-702 caused increased apoptosis compared to OBP-301 or a replication-deficient adenovirus expressing the p53 gene (Ad-p53) in H358 and T.Tn cells. Adenovirus E1A-mediated p21 and MDM2 downregulation was involved in the apoptosis caused by OBP-702. Moreover, OBP-702 significantly suppressed tumour growth in subcutaneous tumour xenograft models compared to monotherapy with OBP-301 or Ad-p53. Our data demonstrated that OBP-702 infection expressed adenovirus E1A and then inhibited p21 and MDM2 expression, which in turn efficiently induced apoptotic cell death. This novel apoptotic mechanism suggests that the p53-expressing OBP-702 is a promising antitumour reagent for human cancer and could improve the clinical outcome. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejca.2011.12.020

Synergistic interaction of telomerase-specific oncolytic virotherapy and chemotherapeutic agents for human cancer

Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

Current Pharmaceutical Biotechnology 13 ( 9 ) 1809 - 1816 2012.7

Language：English

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials
data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer. © 2012 Bentham Science Publishers.

DOI： 10.2174/138920112800958887

Circulating tumour cells detected by a novel adenovirus-mediated system may be a potent therapeutic marker in gynaecological cancers

M. Takakura, S. Kyo, M. Nakamura, Y. Maida, Y. Mizumoto, Y. Bono, X. Zhang, Y. Hashimoto, Y. Urata, T. Fujiwara, M. Inoue

BRITISH JOURNAL OF CANCER 107 ( 3 ) 448 - 454 2012.7

Language：English Publisher：NATURE PUBLISHING GROUP

BACKGROUND: Recently developed detection system for circulating tumour cells (CTCs) using a telomerase-specific replicative adenovirus generated nonspecific green fluorescent protein (GFP) signals because of the co-presence of white blood cells (WBCs) nonspecifically infected by viruses. Here, we established a unique detection system for CTCs that completely excludes nonspecific signals.
METHODS: Blood obtained from the patients was subjected to haemolytic processes to eliminate red blood cells. The cell pellets were then infected with OBP-401, fixed, incubated with fluorescence-labelled anti-CD45 antibody to mark white blood WBCs, and examined on slides under a microscope.
RESULTS: Preparatory experiments with cancer cells artificially added to healthy donor samples confirmed that CD45 labelling could distinguish GFP-positive cancer cells from WBCs. In 53 patients with gynaecological cancers, CTCs were detected in 21 patients (39.6%) when CD45-positive cells were excluded as WBCs among GFP-positive cells. No CTCs were detected in samples from healthy volunteers. There was no significant correlation between CTC counts and known clinicopathological factors. The CTCs rapidly vanished after surgery or chemotherapy in most patients whose treatments were effective. In contrast, the persistence of CTCs even after treatments was tightly associated with poor response to the treatments (P<0.005).
CONCLUSION: The presence of CTCs in our system may potentially be a novel therapeutic marker in gynaecological cancers. British Journal of Cancer (2012) 107, 448-454. doi: 10.1038/bjc.2012.276 www.bjcancer.com Published online 26 June 2012 (C) 2012 Cancer Research UK

DOI： 10.1038/bjc.2012.276

Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

Hui-fang Hao, Munenori Takaoka, Xiao-hong Bao, Zhi-gang Wang, Yasuko Tomono, Kazufumi Sakurama, Toshiaki Ohara, Takuya Fukazawa, Tomoki Yamatsuji, Toshiyoshi Fujiwara, Yoshio Naomoto

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 423 ( 4 ) 744 - 749 2012.7

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.06.030

Branched-chain amino acid-enriched nutrients improve nutritional and metabolic abnormalities in the early post-transplant period after living donor liver transplantation

Ryuichi Yoshida, Takahito Yagi, Hiroshi Sadamori, Hiroaki Matsuda, Susumu Shinoura, Yuzo Umeda, Daisuke Sato, Masashi Utsumi, Takeshi Nagasaka, Nami Okazaki, Ai Date, Ayako Noguchi, Akemi Tanaka, Yuko Hasegawa, Yachiyo Sakamoto, Toshiyoshi Fujiwara

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 19 ( 4 ) 438 - 448 2012.7

Language：English Publisher：SPRINGER TOKYO

Malnutrition and metabolic disorder of patients undergoing living donor liver transplantation (LDLT) can affect post-transplant prognosis. The aim of this study was to establish whether perioperative usage of branched-chain amino-acid (BCAA)-enriched nutrients improve metabolic abnormalities of patients undergoing LDLT.
We designed a randomized pilot study (UMIN registration number; 000004323). Twenty-five consecutive adult elective LDLT recipients were enroled and divided into two groups: the BCAA group (BCAA-enriched nutrients, n = 12) and the control group (standard diet, n = 13). Metabolic and nutritional parameters, including BCAA-to-tyrosine ratio (BTR), retinol binding protein (RBP), and prealbumin were regularly measured from 1 week before to 4 weeks after LDLT. Non-protein respiratory quotient (npRQ) was measured before and 4 weeks after LDLT.
BTR and RBP improved considerably in the BCAA group compared with the controls. npRQ significantly increased from 1 week before LDLT to 4 weeks after LDLT in the BCAA group (0.77 +/- A 0.05 to 0.84 +/- A 0.06, P = 0.002), but not in the control group (0.78 +/- A 0.04 to 0.81 +/- A 0.05).
Supplementation with BCAA-enriched nutrients might improve persistent nutritional and metabolic disorders associated with end-stage liver disease in the early post-transplant period, and consequently shorten the post-transplant catabolic phase after LDLT. A larger multicenter trial is needed to confirm these findings.

DOI： 10.1007/s00534-011-0459-5

Esophageal Cancer Exhibits Resistance to a Novel IGF-1R Inhibitor NVP-AEW541 with Maintained RAS-MAPK Activity

Xiao-Hong Bao, Munenori Takaoka, Hui-Fang Hao, Zhi-Gang Wang, Takuya Fukazawa, Tomoki Yamatsuji, Kazufumi Sakurama, Dong-Sheng Sun, Takeshi Nagasaka, Toshiyoshi Fujiwara, Yoshio Naomoto

ANTICANCER RESEARCH 32 ( 7 ) 2827 - 2834 2012.7

Language：English Publisher：INT INST ANTICANCER RESEARCH

Aim: To assess the effects of a novel type 1 insulin-like growth factor receptor (IGF-1R) inhibitor, NVP-AEW541, on cell proliferation and signal transduction of esophageal cancer. Materials and Methods: Cell proliferation assay and western blot were conducted to assess the antitumor effects of NVP-AEW541. Genetic modification of RAS by expression vector was applied for overexpression of mutant RAS. Results: More than 2 mu mol/l of NVP-AEW541 was required to effectively, inhibit the proliferation of esophageal cancer NVP-AEW541 potently blocked the activation of IGF-IR and protein kinase B (PKB, also known as AKT), but not of mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinases (ERK). Active RAS was not reduced by NVP-AEW541 in esophageal cancer cells TE-1, suggesting that insensitivity of esophageal cancer to NVP-AEW541 is due to the maintained RAS-MAPK activity, which did not arise from RAS mutation. Moreover, the transduction of mutant RAS reduced the sensitivity of TE-1 cells to NVP-AEW541. Conclusion: Stimulation of RAS-MAPK pathway is associated with resistance to NVP-AEW541 in esophageal cancer. Combining NVP-AEW541 with inhibitors/antibodies against RAS-MAPK signaling molecules might be more effective for use against esophageal cancer.

Synergistic Interaction of Telomerase-Specific Oncolytic Virotherapy and Chemotherapeutic Agents for Human Cancer

Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

CURRENT PHARMACEUTICAL BIOTECHNOLOGY 13 ( 9 ) 1809 - 1816 2012.7

Language：English Publishing type：Book review, literature introduction, etc. Publisher：BENTHAM SCIENCE PUBL LTD

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials; data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer.

DOI： 10.2174/138920112800958887

The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment

Yuuri Hashimoto, Hiroshi Tazawa, Fuminori Teraishi, Toru Kojima, Yuichi Watanabe, Futoshi Uno, Shuya Yano, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

PLOS ONE 7 ( 6 ) 1 - 10 2012.6

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1 alpha and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.

DOI： 10.1371/journal.pone.0039292

Carcinosarcoma of the Gallbladder Manifesting as Cholangitis Due to Hemobilia

Hiroshi Sadamori, Hiroyasu Fujiwara, Takehiro Tanaka, Hiroyuki Yanai, Daisuke Satoh, Takahito Yagi, Toshiyoshi Fujiwara

JOURNAL OF GASTROINTESTINAL SURGERY 16 ( 6 ) 1278 - 1281 2012.6

Language：English Publisher：SPRINGER

Carcinosarcomas of the gallbladder are rare tumors that are characterized by malignant epithelial and mesenchymal components, and preoperative diagnosis of carcinosarcoma of the gallbladder remains difficult.
We recently encountered a case of carcinosarcoma of the gallbladder with osteoid and chondroid differentiation, manifesting as cholangitis due to hemobilia.
Preoperative computed tomography and magnetic resonance imaging indicated the cause of cholangitis and provided qualitative information regarding the two components of the tumor.

DOI： 10.1007/s11605-012-1836-3

Long-term outcome of induction chemoradiotherapy with docetaxel and cisplatin followed by surgery for non-small-cell lung cancer with mediastinal lymph node metastasis

Shinichi Toyooka, Katsuyuki Kiura, Mitsuhiro Takemoto, Takahiro Oto, Nagio Takigawa, Toshiyoshi Fujiwara, Shinichiro Miyoshi, Hiroshi Date

INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 14 ( 5 ) 565 - 569 2012.5

Language：English Publisher：OXFORD UNIV PRESS

The purpose of this study was to show the long-term outcome of induction chemoradiotherapy, using docetaxel and cisplatin with concurrent radiotherapy followed by surgery for non-small-cell lung cancer (NSCLC) with mediastinal nodal metastasis. Between January 2000 and July 2006, 22 consecutive NSCLC patients with pathologically proven mediastinal nodal metastasis were treated with tri-modality therapy. The regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40-46 Gy. The induction therapy was followed by surgery 4-6 weeks later. The pulmonary resections were composed of a lobectomy in 19 patients, including 3 with a sleeve lobectomy, a bilobectomy in 2 patients and a left pneumonectomy in 1 patient. With a median follow-up duration of 8.7 years, the 3-year and 7-year overall survival (OS) rates for the entire population were 72.7 and 63.6%, respectively. Our results suggest that tri-modality therapy is promising for NSCLC patients with mediastinal nodal metastasis.

DOI： 10.1093/icvts/ivs028

Chemotherapy of methioninase-synchronized S/G2 phase-blocked cancer cells identified by cell cycle-specific fluorescent reporters

Shuya Yano, Shukuan Li, Qinghong Han, Yuying Tan, Toshiyoshi Fujiwara, Robert M. Hoffman

JOURNAL OF CLINICAL ONCOLOGY 30 ( 15 ) 2012.5

腺様嚢胞癌細胞株におけるテロメラーゼ特異的腫瘍融解ウイルスの抗腫瘍効果の検討

佐藤大典, 栗原祐史, 近藤誠二, 代田達夫, 浦田泰生, 藤原俊義, 新谷悟

頭頸部癌 38 ( 2 ) 225 - 225 2012.5

Resection of Metachronous Lymph Node Metastases from Hepatocellular Carcinoma after Hepatectomy: Report of Four Cases

Masashi Utsumi, Hiroaki Matsuda, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Satoh, Masaaki Hashimoto, Takahito Yagi, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 66 ( 2 ) 177 - 182 2012.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

We report 4 cases of surgical resection of metachronous lymph node (LN) metastases from hepatocellular carcinoma (HCC) following hepatectomy. Clinicopathological features and results of LN dissection were investigated in the 4 patients. One patient was found to have a single metastasis in the mediastinal LNs, another had multiple metastases in the mediastinal and abdominal LNs, and the other 2 had single metastases in the abdominal LN. The locations of the abdominal LN metastases were behind the pancreas head in 2 patients and around the abdominal aorta in 1 patient. They all underwent surgical resection of metastatic LNs and had no postoperative complications. The 3 patients whose LN metastases were solitary have been alive for more than 2 years after LN resection, and one of them is free from recurrence. The patient with multiple LN metastases died 13 months after LN resection due to carcinomatosis. With the expectation of long-term survival, a single metachronous LN metastasis from HCC after hepatectomy should be resected in patients without uncontrollable intrahepatic or extrahepatic tumors.

DOI： 10.18926/AMO/48268

Iron chelator contributes to anti-angiogenic therapy via selective induction of VEGF-A

Toshiaki Ohara, Kazuhiro Noma, Seishi Nishitani, Shinichiro Watanabe, Yasuko Tomono, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 72 2012.4

Inhibitory effect of oncolytic adenovirus on transforming growth factor-beta-induced epithelial-mesenchymal transition in human cancer cells

Yuuri Hashimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 72 2012.4

Ataxia-Telangiectasia Mutated and the Mre11-Rad50-NBS1 Complex: Promising Targets for Radiosensitization

Shinji Kuroda, Yasuo Urata, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 66 ( 2 ) 83 - 92 2012.4

Language：English Publishing type：Book review, literature introduction, etc. Publisher：OKAYAMA UNIV MED SCHOOL

Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several chemotherapeutic agents have the potential to increase the radiosensitivity of tumor cells, investigators have also studied a number of molecularly targeted agents as radiosensitizers in clinical trials based on reasonably promising preclinical data. Recent intense research into the DNA damage-signaling pathway revealed that ataxia-telangiectasia mutated (ATM) and the Mre11-Rad50-NBS1 (MRN) complex play central roles in DNA repair and cell cycle checkpoints and that these molecules are promising targets for radiosensitization. Researchers recently developed three ATM inhibitors (KU-55913, CGK733, and CP466722) and an MRN complex inhibitor (mirin) and showed that they have great potential as radiosensitizers of tumors in preclinical studies. Additionally, we showed that a telomerase-dependent oncolytic adenovirus that we developed (OBP-301 [telomelysin]) produces profound radiosensitizing effects by inhibiting the MRN complex via the adenoviral E1B55kDa protein. A recent Phase I trial in the United States determined that telomelysin was safe and well tolerated in humans, and this agent is about to be tested in combination with radiotherapy in a clinical trial based on intriguing preclinical data demonstrating that telomelysin and ionizing radiation can potentiate each other. In this review, we highlight the great potential of ATM and MRN complex inhibitors, including telomelysin, as radiosensitizing agents.

DOI： 10.18926/AMO/48258

Preventive Effect of Omental Flap in Pancreaticoduodenectomy against Postoperative Pseudoaneurysm Formation

Hiroaki Matsuda, Hiroshi Sadamori, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Satoh, Masashi Utsumi, Takahito Yagi, Toshiyoshi Fujiwara

HEPATO-GASTROENTEROLOGY 59 ( 114 ) 578 - 583 2012.3

Language：English Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: An omental flap covering the splanchnic vessels might reduce postoperative intra-abdominal hemorrhage after pancreaticoduodenectomy. However, the efficiency of such a procedure remains to be verified. The purpose of this study was to determine the effect of mental flap placement in pancreaticoduodenectomy on the incidence of postoperative pseudoaneurysms. Methodology: Of 229 consecutive patients who underwent pancreaticoduodenectomy, the most recent 157 patients received the omental flap, while the initial 72 patients had no omental flap placement. Various preoperative factors were considered in the evaluation (age, gender, body mass index, primary disease and concurrent disease), as well as operative factors (operation time, blood loss, operative procedures, pancreatic texture, size of pancreatic duct and surgeon's experience). Results: Eighty-one patients (35.4%) developed pancreatic fistula. Nine patients (3.9%) developed postoperative pseudoaneurysm. Among the patients with pancreatic fistula, those without omental flap developed pseudoaneurysms more frequently (21.7%) than those with omental flap placement (5.2%). Multivariate analysis identified pancreatic fistula, no use of mental flap and hypertension, in that order, as predisposing factors for a pseudoaneurysm. The omental flap significantly prevented pseudoaneurysms (p=0.021; OR=0.151; 95% CI, 0.030-0.751). Conclusions: Omental flap placement over splanchnic vessels could be a feasible and efficient surgical procedure to prevent postoperative pseudoaneurysms following pancreaticoduodenectomy.

DOI： 10.5754/hge11452

Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

Daisuke Nobuoka, Yutaka Motomura, Hirofumi Shirakawa, Toshiaki Yoshikawa, Toshimitsu Kuronuma, Mari Takahashi, Kohei Nakachi, Hiroshi Ishii, Junji Furuse, Naoto Gotohda, Shinichiro Takahashi, Toshio Nakagohri, Masaru Konishi, Taira Kinoshita, Hiroyuki Komori, Hideo Baba, Toshiyoshi Fujiwara, Tetsuya Nakatsura

INTERNATIONAL JOURNAL OF ONCOLOGY 40 ( 1 ) 63 - 70 2012.1

Language：English Publisher：SPANDIDOS PUBL LTD

Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemoembolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pretreatment and post-treatment by an interferon-gamma enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P=0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC.

DOI： 10.3892/ijo.2011.1202

胃癌術後脊椎転移による横断性脊髄障害を呈した1例.

河野藍子, 香川俊輔, 岸本浩行, 宇野太, 西崎正彦, 大岩雅彦, 藤原俊義

癌と化学療法 39 ( 12 ) 2357 - 2359 2012

Language：Japanese Publisher：(株)癌と化学療法社

症例は45歳、男性。心窩部痛・体重減少を主訴に発見された進行胃癌に対して幽門側胃切除術、D2、Roux-en Y再建を行い、術後診断はpT4aN3bCY1、stage IVであった。術後S-1による化学療法を施行中、術後3ヵ月に背部痛が出現した。PET-CTではTh4-6の骨転移を指摘された。直ちに骨転移に対し放射線療法を開始したが、第5治療日より脊髄横断症状を呈し座位保持も不能となった。その後、癒着性の小腸イレウスが発症し小腸部分切除術を施行することとなり、同時に直腸肛門機能低下による排便困難に対しS状結腸ストーマ造設を併施した。その結果、排便の自己管理が可能になり、さらに放射線治療の完遂ならびに、その後の化学療法と緩和治療が在宅で可能であった。胃癌の骨転移はまれであるが、その予後は極めて不良である。胃癌の骨転移の特徴・対策を知り、早期診断と集学的治療は重要であり、本症例の経験に文献的考察を加え報告する。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20121206360200&doc_link_id=%2Fab8gtkrc%2F2012%2F003912%2F200%2F2357-2359%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003912%2F200%2F2357-2359%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Gastric aberrant pancreas with acute pancreatitis treated with surgery

124 ( 1 ) 59 - 62 2012

Pathological complete response of advanced gastric cancer with pyloric stenosis to neoadjuvant S-1/CDDP chemotherapy : A case report

124 ( 1 ) 63 - 66 2012

Intractable Bile Leakage after Hepatectomy for Hepatocellular Carcinoma in 359 Recent Cases

Hiroshi Sadamori, Takahito Yagi, Hiroaki Matsuda, Susumu Shinoura, Yuzo Umeda, Toshiyoshi Fujiwara

DIGESTIVE SURGERY 29 ( 2 ) 149 - 156 2012

Language：English Publisher：KARGER

Background/Aims: Bile leakage is still a common cause of major morbidity after hepatectomy for hepatocellular carcinoma (HCC). The purpose of this study was to identify characteristics and risk factors for intractable bile leakage after hepatectomy for HCC. Methods: Risk factors for bile leakage were analyzed in 359 patients who underwent hepatectomy for HCC between 2001 and 2010. The causes, management and outcomes of intractable bile leakage which needed endoscopic therapy or percutaneous transhepatic biliary drainage were investigated. Results: A total of 296 patients (82.5%) underwent an anatomic hepatectomy, and a repeat hepatectomy was carried out in 59 patients (16.4%). The prevalence of bile leakage was 12.8%, and 8 patients had intractable bile leakage. An operative time >= 300 min was an independent risk factor for bile leakage after hepatectomy for HCC. The main causes of intractable bile leakage were a latent stricture of the biliary anatomy caused by previous treatments for HCC and intraoperative injury of the hepatic duct related to repeat hepatectomy. Conclusion: To help prevent intractable bile leakage, a preoperative assessment of the biliary anatomy and surgical procedures to decrease the incidence of major bile leakage should be considered for selected patients with a high risk for intractable bile leakage. Copyright (c) 2012 S. Karger AG, Basel

DOI： 10.1159/000337313

大学病院におけるrobotic surgery導入の経験.

香川俊輔, 西崎正彦, 宇野太, 岸本浩行, 藤原俊義

外科 74 ( 8 ) 809 - 812 2012

A case of esophageal carcinosarcoma with a component of small cell carcinoma

Tanabe Shunsuke, Fujiwara Toshiyoshi, Shirakawa Yasuhiro, Maeda Naoaki, Ohara Toshiaki, Noma Kazuhiro, Sakurama Kazufumi, Yanai Hiroyuki, Yamatsuji Tomoki, Naomoto Yoshio

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 124 ( 2 ) 145 - 148 2012

Language：Japanese Publisher：Okayama Medical Association

We experienced a case of esophageal carcinosarcoma with a component of small cell carcinoma. The patient was a 73-year-old man. We administered chemotherapy of CDDP+VP-16, and performed an operation after 2 courses of this chemotherapy. Subtotal esophagectomy and reconstruction with the small intestine was performed. More than three years after resection, he remains alive and recurrence-free. There are few cases of esophageal carcinosarcoma and small cell carcinoma. We report this rare case herein.

DOI： 10.4044/joma.124.145

胃癌術後腹膜播種による十二指腸閉塞に対して内視鏡的ステント留置術が奏効した1例.

大岩雅彦, 香川俊輔, 岸本浩行, 宇野太, 西崎正彦, 河野藍子, 藤原俊義

癌と化学療法 39 ( 12 ) 2372 - 2374 2012

Language：Japanese Publisher：(株)癌と化学療法社

症例は79歳、男性。十二指腸潰瘍の手術既往による残胃の吻合部に残胃癌を指摘され、残胃部分切除・Roux-en-Y再建を行った。術後Treitz靱帯近傍に再発腫瘍を指摘され、化学療法を施行中に腸閉塞症状が出現した。CTで十二指腸の著明な拡張を認め、既知の再発腫瘍によるY脚部の通過障害と診断した。閉塞部位が一ヶ所であったことから、ダブルバルーン小腸内視鏡を用い狭窄部にステントを留置した。ステント留置後腸閉塞は解除され、経口摂取と化学療法の再開が可能となった。近年普及してきたダブルバルーン内視鏡により従来困難であったRoux-en-Y再建後の十二指腸側Y脚へのアプローチが可能となった。本症例では狭窄部へのステント留置により手術を回避し得たことから、緩和治療として悪性腸閉塞症治療の1選択肢になり得ると考え報告する。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20121206360205&doc_link_id=%2Fab8gtkrc%2F2012%2F003912%2F205%2F2372-2374%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003912%2F205%2F2372-2374%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A telomerase-specific oncolytic virotherapy for gastric cancer stem cells

KAGAWA Shunsuke, YANO Shuya, FUJIWARA Toshiyoshi

Cytometry Research 22 ( 2 ) 21 - 25 2012

Language：Japanese Publisher：Japan Cytometry Society

<p>Since cancer stem cells show their resistance to chemo- and radiotherapy, they are thought to be correlated with the treatment resistance of many cancers, and thus help explain recurrence and advanced disease. Here, we examined the therapeutic effect of a genetically engineered telomerase specific oncolytic adenovirus, Telomelysin, (OBP-301) against cancer stem cells. OBP-301 killed CD133+ human gastric cancer, which have a stem cell-like phenotype, more efficiently than conventional therapies. Visualization of cell-cycle behavior in living cells by Fucci showed that tumor spheres of CD133+ cells maintained a G0/G1 state, and that OBP-301 then killed them through virus-induced S phase transition. Mobilization of quiescent CSCs may sensitize them to cell death signals.</p>

DOI： 10.18947/cytometryresearch.22.2_21

当科における咽頭喉頭食道全摘症例の検討

田辺俊介, 白川靖博, 青山克幸, 前田直見, 大原利章, 櫻間教文, 野間和広, 藤原俊義

General Thoracic and Cardiovascular Surgery 60 ( Supplement ) 2012

食道癌における除鉄による遊走,浸潤能抑制作用の検討

浦野真一, 大原利章, 前田直見, 渡辺伸一郎, 田辺俊介, 野間和広, 友野靖子, 白川康博, 木村文昭, 藤原俊義

日本鉄バイオサイエンス学会学術集会プログラム・抄録集 36th 2012

腹部食道癌に対して左開胸開腹連続切開および観音開き法食道残胃吻合を行った1症例

野間和広, 白川靖博, 青山克幸, 前田直見, 大原利章, 田辺俊介, 西崎正彦, 香川俊輔, 藤原俊義

General Thoracic and Cardiovascular Surgery 60 ( Supplement ) 2012

当院でのPERIOによる胸部食道癌周術期管理の取り組みについての検討

白川靖博, 青山克幸, 前田直見, 田辺俊介, 大原利章, 野間和広, 櫻間教文, 藤原俊義

General Thoracic and Cardiovascular Surgery 60 ( Supplement ) 2012

特集：最新の疾患バイオマーカー研究大腸がん.

永坂岳司, 母里淑子, 楳田祐三, 藤原俊義

日本臨床 70 ( 5 ) 802 - 807 2012

アカデミアにおける探索的医薬品開発の方向性 -国産ウイルス製剤の米国での臨床試験への道程-.

藤原俊義

薬理と治療 40 ( 4 ) 303 - 304 2012

食事・栄養指導 1前編.

田辺俊介, 宇野太, 近藤喜太, 藤原俊義

消化器外科NURSING 17 ( 8 ) 82 - 85 2012

Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas

124 ( 2 ) 105 - 110 2012

糞便を用いた大腸がんの遺伝子診断（2）～便中メチル化CpG検出による大腸がんスクリーニング～.

永坂岳司, 藤原俊義

大腸癌Frontier 5 50 - 57 2012

糖尿病における移植療法の現状.

野口洋文, 藤原俊義

岡山医学会雑誌 124 ( 3 ) 249 - 252 2012

頸胸境界部進行食道癌に対するDoor open法によるアプローチ

山辻知樹, 木下真一郎, 山田貴子, 高岡宗徳, 深澤拓也, 林次郎, 繁光薫, 吉田和弘, 森田一郎, 田邉俊介, 藤原康宏, 野間和広, 櫻間教文, 白川靖博, 松岡順治, 藤原俊義, 羽井佐実, 猶本良夫

日本外科学会雑誌 113 2012

当院における胃上部早期胃癌に対する噴門側胃切除・食道残胃吻合術の検討

宇野太, 香川俊輔, 西崎正彦, 岸本浩行, 白川靖博, 永坂岳司, 野間和広, 田邊俊介, 合地明, 藤原俊義

日本消化器外科学会雑誌(Web) 45 ( Supplement1 ) 2012

パラチノースを主糖質源とした調整流動食MHN-01による食道癌周術期管理の有用性-基礎実験から臨床研究まで-

山辻知樹, 平林葉子, 高岡宗徳, 林次郎, 深澤拓也, 繁光薫, 吉田和弘, 大原利章, 田辺俊介, 野間和広, 白川靖博, 藤原俊義, 中島一毅, 森田一郎, 猶本良夫

General Thoracic and Cardiovascular Surgery 60 ( Supplement ) 2012

心房中隔欠損症による肺高血圧症を合併した食道癌切除の経験

大原利章, 白川靖博, 青山克幸, 前田直見, 田辺俊介, 野間和広, 藤原俊義

General Thoracic and Cardiovascular Surgery 60 ( Supplement ) 2012

F-18 FDG PET/CT Contributes to More Accurate Detection of Lymph Nodal Metastasis From Actively Proliferating Esophageal Squamous Cell Carcinoma

Shunsuke Tanabe, Yoshio Naomoto, Yasuhiro Shirakawa, Yasuhiro Fujiwara, Kazufumi Sakurama, Kazuhiro Noma, Munenori Takaoka, Tomoki Yamatsuji, Takao Hiraki, Yoshihiro Okumura, Masahiko Mitani, Mitsumasa Kaji, Susumu Kanazawa, Toshiyoshi Fujiwara

CLINICAL NUCLEAR MEDICINE 36 ( 10 ) 854 - 859 2011.10

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

Purpose: Evaluating the status of disease progression is critical for planning a therapeutic strategy for esophageal cancer. In this regard, F-18 fluorodeoxyglucose-labeled positron emission tomography (PET) is one of the most useful diagnostic modalities. However, there is room to improve its diagnostic performance, such as distinguishing lymph nodal metastases from false positives. In this study, we examined the diagnostic accuracy of fluorodeoxyglucose PET accompanied by computed tomography imaging (PET/CT) to detect regional lymph nodal metastasis from esophageal squamous cell carcinoma (ESCC).
Methods: A total of 102 patients diagnosed as ESCC were subjected to this study. These patients had a preoperative PET/CT examination to evaluate the existence of metastasis. The values of maximum standardized uptake value (SUVmax) in primary tumors and in metastasized lymph nodes were measured to analyze their relationship with various clinicopathologic characteristics including the status of tumor cell proliferation, which was assessed by immunohistochemistry for Ki-67.
Results: The SUVmax of the primary tumor was positively correlated with tumor size and vessel invasion, and was positively related with the SUVmax of lymph nodal metastasis, especially in cases of poorly differentiated ESCC. The SUVmax of metastasized lymph nodes was higher in larger-sized metastasized lymph nodes, whereas the Ki-labeling index of lymph nodal metastasis was positively related with the SUVmax per unit area (SUVmax/mm(2)). The diagnostic accuracy of PET/CT (87.3%) was higher than that of conventional CT scans (78.4%).
Conclusions: The improved diagnostic accuracy of PET/CT can be explained by its ability to detect actively progressive metastasis at an early phase regardless of size.

DOI： 10.1097/RLU.0b013e318217adc9

当院における頭頸部癌・食道癌領域におけるPEGの適応と現状

田辺俊介, 白川靖博, 野間和広, 前田直見, 大原利章, 櫻間教文, 浅野博昭, 岸本浩行, 宇野太, 西崎正彦, 佃和憲, 香川俊輔, 藤原俊義, 小野田友男, 勝井邦彰, 片山敬久, 吉尾浩太郎, 武本充広

Gastroenterological Endoscopy 53 ( Suppl.2 ) 2784 - 2784 2011.9

Tumor-selective adenoviral-mediated GFP genetic labeling of human cancer in the live mouse reports future recurrence after resection

Hiroyuki Kishimoto, Ryoichi Aki, Yasuo Urata, Michael Bouvet, Masashi Momiyama, Noriaki Tanaka, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 10 ( 16 ) 2737 - 2741 2011.8

Language：English Publisher：LANDES BIOSCIENCE

We have previously developed a telomerase-specific replicating adenovirus expressing GFP (OBP-401), which can selectively label tumors in vivo with GFP. Intraperitoneal (i.p.) injection of OBP-401 specifically labeled peritoneal tumors with GFP, enabling fluorescence visualization of the disseminated disease and real-time fluorescence surgical navigation. However, technical problems of removing all cancer cells still remain, even with fluorescence-guided surgery. In this study, we report that in vivo OBP-401 labeling of tumors with GFP before fluorescence-guided surgery reports cancer recurrence after surgery. Recurrent tumor nodules brightly expressed GFP, indicating that initial OBP-401-GFP labeling of peritoneal disease was genetically stable such that proliferating residual cancer cells still express GFP. In situ tumor labeling with a genetic reporter has important advantages over antibody and other non-genetic labeling of tumors, since residual disease remains labeled during recurrence and can be further resected under fluorescence guidance.

DOI： 10.4161/cc.10.16.16756

末梢型と肝門型肝内胆管癌における術式の検討

佐藤太祐, 楳田祐三, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 内海方嗣, 杭瀬崇, 菊池寛次, 八木孝仁, 藤原俊義

岡山医学会雑誌 123 ( 2 ) 168 - 168 2011.8

Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells

Toshiaki Ohara, Munenori Takaoka, Shinichi Toyooka, Yasuko Tomono, Toshio Nishikawa, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

CANCER SCIENCE 102 ( 7 ) 1344 - 1349 2011.7

Language：English Publisher：WILEY-BLACKWELL

Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of < 1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0)/G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3); P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival. (Cancer Sci 2011; 102: 1344-1349)

DOI： 10.1111/j.1349-7006.2011.01967.x

高度脈管侵襲を伴う肝細胞癌に対する治療戦略高度脈管侵襲肝癌に対する治療戦略 Vp3/4、Vv2/3進行肝癌の治療成績

杭瀬崇, 楳田祐三, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 八木孝仁, 藤原俊義

日本消化器外科学会総会 66回 200 - 200 2011.7

当院で切除した膵内分泌腫瘍に対する治療成績

内海方嗣, 松田浩明, 杭瀬崇, 佐藤太祐, 吉田龍一, 楳田祐三, 篠浦先, 貞森裕, 八木孝仁, 藤原俊義

日本消化器外科学会総会 66回 314 - 314 2011.7

Efficient virotherapy for osteosarcoma by telomerase-specific oncolytic adenovirus

Guidong Li, Hiroyuki Kawashima, Akira Ogose, Takashi Ariizumi, Yongjun Xu, Tetsuo Hotta, Yasuo Urata, Toshiyoshi Fujiwara, Naoto Endo

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 137 ( 6 ) 1037 - 1051 2011.6

Language：English Publisher：SPRINGER

A telomerase-specific oncolytic adenovirus, Telomelysin, can selectively kill cancer cells, and be attenuated in normal cells. We herein describe the oncolytic effect of Telomelysin on human osteosarcoma both in vitro and in vivo.
The anti-tumor effects of Telomelysin were evaluated on human osteosarcoma cell lines in vitro and in a mouse xenograft model of human osteosarcoma in vivo. The replication efficiencies of Telomelysin in human osteosarcoma cell lines and normal cell lines and in osteosarcoma xenografts were determined by the expression levels of E1 mRNA and E1A protein using real-time quantitative PCR, Western blot analysis and immunohistochemistry. The in vitro telomerase-specific replication and the viral infection rate were also confirmed by TelomeScan (Telomelysin-GFP), using fluorescent microscopy and flow cytometry, respectively. The cell viabilities were examined by XTT assay, and the tumor volumes were measured every 2 days. The induction of apoptosis was assessed by Western blot analysis, as well as by TUNEL assay.
TelomeScan and Telomelysin were efficiently replicated in human osteosarcoma cell lines and led to a dose- and time-dependent expression of GFP, E1 mRNA and E1A protein. Telomelysin infection induced marked cytolysis and apoptosis in osteosarcoma cell lines in vitro. Neither cytotoxicity nor apoptosis were induced in normal human cell lines. In the human osteosarcoma cell xenograft model, intratumoral injection of Telomelysin resulted in increased viral replication, significant tumor growth suppression and distinct apoptotic cell death.
This study indicated that virotherapy with Telomelysin may provide a promising strategy for the treatment of human osteosarcoma.

DOI： 10.1007/s00432-010-0969-6

IS-9-3 Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2 extracellular domain in breast cancer cells(IS-9 Translational research in breast cancer treatment)

Yoshida Ryosuke

Journal of Japan Surgical Society 112 ( 1 ) 202 - 202 2011.5

PS-091-7 腹膜播種を伴う進行・再発胃癌患者を対象としたDocetaxelとS-1の併用化学療法の検討(臨床第II相試験)(PS-091 ポスターセッション(91)胃:化学療法-3,第111回日本外科学会定期学術集会)

宇野太, 香川俊輔, 西崎正彦, 合地明, 木村臣一, 高畑隆臣, 野中泰幸, 二宮基樹, 藤原俊義

日本外科学会雑誌 112 ( 1 ) 663 - 663 2011.5

Enhanced Safety Profiles of the Telomerase-Specific Replication-Competent Adenovirus by Incorporation of Normal Cell-Specific microRNA-Targeted Sequences

Kumiko Sugio, Fuminori Sakurai, Kazufumi Katayama, Katsuhisa Tashiro, Hayato Matsui, Kenji Kawabata, Atsushi Kawase, Masahiro Iwaki, Takao Hayakawa, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

CLINICAL CANCER RESEARCH 17 ( 9 ) 2807 - 2818 2011.5

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Oncolytic adenoviruses (Ad) have been actively pursued as potential agents for cancer treatment. Among the various types of oncolytic Ads, the telomerase-specific replication-competent Ad (TRAD), which possesses an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, has shown promising results in human clinical trials; however, the E1 gene is also slightly expressed in normal cells, leading to replication of TRAD and cellular toxicity in normal cells.
Experimental Design: To overcome this problem, we utilized a microRNA (miRNA)-regulated gene expression system. Four copies of complementary sequences for miR-143, -145, -199a, or let-7a, which have been reported to be exclusively downregulated in tumor cells, were incorporated into the 3'-untranslated region of the E1 gene expression cassette.
Results: Among the TRAD variants (herein called TRADs) constructed, TRADs containing the sequences complementary to miR-143, -145, or -199a showed efficient oncolytic activity comparable to the parental TRAD in the tumor cells. On the other hand, replication of the TRADs containing the miRNA complementary sequences was at most 1,000-fold suppressed in the normal cells, including primary normal cells. In addition, to suppress the replication of the TRADs in hepatocytes as well as other normal cells, we constructed a TRAD containing 2 distinct complementary sequences for miR-199a and liver-specific miR-122a (TRAD-122a/199aT). TRAD-122a/199aT exhibited more than 10-fold reduction in viral replication in all the normal cells examined, including primary hepatocytes.
Conclusions: This study showed that oncolytic Ads containing the sequences complementary to normal cell-specific miRNAs showed significantly improved safety profiles without altering tumor cell lysis activity. Clin Cancer Res; 17(9); 2807-18. (C)2011 AACR.

DOI： 10.1158/1078-0432.CCR-10-2008

再発肝細胞癌の治療方針再肝切除・RFAの有効性とSalvage transplantation導入の見極め

楳田祐三, 八木孝仁, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 杭瀬崇, 藤原俊義

日本外科学会雑誌 112 ( 臨増1-2 ) 356 - 356 2011.5

大腸癌肝転移の外科的治療戦略術前・術後化学療法の意義と問題点

杭瀬崇, 楳田祐三, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 八木孝仁, 藤原俊義

日本外科学会雑誌 112 ( 臨増1-2 ) 360 - 360 2011.5

Telomerase-specific oncolytic virotherapy for human gastrointestinal cancer

Toshiyoshi Fujiwara, Yasuhiro Shirakawa, Shunsuke Kagawa

EXPERT REVIEW OF ANTICANCER THERAPY 11 ( 4 ) 525 - 532 2011.4

Language：English Publishing type：Book review, literature introduction, etc. Publisher：EXPERT REVIEWS

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85% of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (OBP-301), in which the hTERT promoter element drives the expression of El genes. Since only tumor cells that express telomerase activity are able to activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. In this article we show that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human gastrointestinal malignancies.

DOI： 10.1586/ERA.10.200

Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2 extracellular domain in human breast cancer cells

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 71 2011.4

大腸癌肝転移の外科治療術前・術後化学療法の効果

杭瀬崇, 楳田祐三, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 八木孝仁, 藤原俊義

岡山医学会雑誌 123 ( 1 ) 76 - 76 2011.4

手術手技膵頭十二指腸切除術における血管床に対する大網弁被覆の意義

松田浩明, 八木孝仁, 藤原俊義

手術 65 ( 3 ) 349 - 352 2011.3

Glutamine depletion induces murine neonatal melena with increased apoptosis of the intestinal epithelium

Takayuki Motoki, Yoshio Naomoto, Junji Hoshiba, Yasuhiro Shirakawa, Tomoki Yamatsuji, Junji Matsuoka, Munenori Takaoka, Yasuko Tomono, Yasuhiro Fujiwara, Hiroshi Tsuchita, Mehmet Gunduz, Hitoshi Nagatsuka, Noriaki Tanaka, Toshiyoshi Fujiwara

WORLD JOURNAL OF GASTROENTEROLOGY 17 ( 6 ) 717 - 726 2011.2

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM: To investigate the possible biological outcome and effect of glutamine depletion in neonatal mice and rodent intestinal epithelial cells.
METHODS: We developed three kinds of artificial milk with different amounts of glutamine; Complete amino acid milk (CAM), which is based on maternal mouse milk, glutamine-depleted milk (GDM), and glutaminerich milk (GRM). GRM contains three-fold more glutamine than CAM. Eighty-seven newborn mice were divided into three groups and were fed with either of CAM, GDM, or GRM via a recently improved nipple-bottle system for seven days. After the feeding period, the mice were subjected to macroscopic and microscopic observations by immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) and Ki-67 as markers of cell proliferation, and for cleaved-caspase-3 as a marker of apoptosis. Moreover, IEC6 rat intestinal epithelial cells were cultured in different concentrations of glutamine and were subject to a 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate cell proliferation assay, flow cytometry, and western blotting to examine the biological effect of glutamine on cell growth and apoptosis.
RESULTS: During the feeding period, we found colonic hemorrhage in six of 28 GDM-fed mice (21.4%), but not in the GRM-fed mice, with no differences in body weight gain between each group. Microscopic examination showed destruction of microvilli and the disappearance of glycocalyx of the intestinal wall in the colon epithelial tissues taken from GDM-fed mice. Intake of GDM reduced BrdU incorporation (the average percentage of BrdU-positive staining; GRM: 13.8%, CAM: 10.7%, GDM: 1.14%, GRM vs GDM: P < 0.001, CAM vs GDM: P < 0.001) and Ki-67 labeling index (the average percentage of Ki-67-positive staining; GRM: 24.5%, CAM: 22.4% GDM: 19.4%, GRM vs GDM: P = 0.001, CAM vs GDM: P =0.049), suggesting that glutamine depletion inhibited cell proliferation of intestinal epithelial cells. Glutamine deprivation further caused the deformation of the nuclear membrane and the plasma membrane, accompanied by chromatin degeneration and an absence of fat droplets from the colonic epithelia, indicating that the cells underwent apoptosis. Moreover, immunohistochemical analysis revealed the appearance of cleaved caspase-3 in colonic epithelial cells of GDM-fed mice. Finally, when IEC6 rat intestinal epithelial cells were cultured without glutamine, cell proliferation was significantly suppressed after 24 h (relative cell growth; 4 mmol/L: 100.0% 36.1%, 0 mmol/L: 25.3% 25.0%, P < 0.05), with severe cellular damage. The cells underwent apoptosis, accompanied by increased cell population in sub-GO phase (4 mmol/L: 1.68%, 0.4 mmol/L: 1.35%, 0 mmol/L: 5.21%), where dying cells are supposed to accumulate.
CONCLUSION: Glutamine is an important alimentary component for the maintenance of intestinal mucosa. Glutamine deprivation can cause instability of the intestinal epithelial alignment by increased apoptosis. (C) 2011 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v17.i6.717

A Prognostic Model and Treatment Strategy for Intrahepatic Recurrence of Hepatocellular Carcinoma after Curative Resection

Yuzo Umeda, Hiroaki Matsuda, Hiroshi Sadamori, Hiroyoshi Matsukawa, Takahito Yagi, Toshiyoshi Fujiwara

WORLD JOURNAL OF SURGERY 35 ( 1 ) 170 - 177 2011.1

Language：English Publisher：SPRINGER

Background The aim of this study was to evaluate the prognostic factors for intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resection.
Methods Of 297 patients with HCC who underwent curative resection between 1998 and 2007, 145 had intrahepatic recurrence, and 125 of these were enrolled in this study. We analyzed the relationships between overall survival after HCC recurrence and 20 variables at initial hepatectomy and recurrence.
Results Recurrent HCC was treated by repeat hepatectomy (Re-Hr, n = 29), radiofrequency ablation (RFA, n = 58), or transarterial chemoembolization (TAE, n = 38). Complete tumor control (CTC) by Re-He and RFA was selected for 70% of patients. RFA-treated patients had more tumors, smaller tumors, and poorer liver function at recurrence than the Re-Hr group. The overall 1-, 3-, and 5-year post-recurrence survival rates (SR) were 93.1, 66.8, 58.1%; 94.7, 75.1, 48.3%; and 80.1, 22.5, 0%, respectively, in the Re-Hr, RFA, and TAE groups. The SR was better for Re-Hr and RFA than for TAE (p < 0.0001). Outcomes were similar in Re-Hr and RFA, regardless of recurrent tumor size. Multivariate analysis identified Child-Pugh grade B, AFP >= 100 ng/ml at recurrence, recurrent tumor size >= 3 cm, tumor number >= 3, and CTC as significant prognostic factors for overall post-recurrence survival. A scoring system using 1 point for each patient-background factor provided a well-categorized predictive model. The overall 3-/5-year post-recurrence SRs were 83.1/59.3%, 64.1/41.9%, 42.0/18.0%, and 13.6/0% at risk number (R) R0, R1, R2, and R3/4, respectively (p < 0.05).
Conclusions Significant prognostic factors for intrahepatic recurrent HCC are poor hepatic reserve, AFP, recurrent tumor size and number, and CTC. Selection of treatment modality for intrahepatic recurrence requires the clinician to be mindful of the predictive factors and to control tumors aggressively by adequate treatment, selected by balancing various conditions.

DOI： 10.1007/s00268-010-0794-8

The 2010 Okayama Medical Association Awards: Radiosensitization by telomerase-dependent oncolytic adenovirus

Journal of Okayama Medical Association 123 ( 2 ) 103 - 109 2011.1

Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis.

Takeda M, Nagasaka T, Dong-Sheng S, Nishie H, Oka T, Yamada E, Mori Y, Shigeyasu K, Morikawa T, Mizobuchi S, Fujiwara T

Acta Med Okayama 2011

肝細胞癌に対する肝切除359例における胆汁漏危険因子の解析.

貞森裕, 八木孝仁, 松田浩明, 篠浦先, 楳田祐三, 吉田龍一, 佐藤太祐, 信岡大輔, 内海方嗣, 吉田一博, 藤原俊義

日本臨床外科学会雑誌 2011

Leukoencephalopathy syndrome after living-donor liver transplantation.

Umeda Y, Matsuda H, Sadamori H, Shinoura S, Yoshida R, Sato D, Utsumi M, Yagi T, Fujiwara T

Exp Clin Transplant 2011

Surgery for cancers at the esophagogastric junction and Barrett's esophageal cancers.

Shirakawa Y, Tanabe S, Noma K, Sakurama K, Fujiwara T

Nihon Rinsho 2011

Prolonged complete response obtained by radiation and chemotherapy with paclitaxel in a case of recurrent gastric cancer in the rectovesical pouch.

Kanaya N, Kagawa S, Uno F, Kunitomi A, Ogawa N, Fujiwara T

Gan To Kagaku Ryoho 2011

The usefulness of pre-radiofrequency ablation SUV(max) in 18F-FDG PET/CT to predict the risk of a local recurrence of malignant lung tumors after lung radiofrequency ablation.

Harada S, Sato S, Suzuki E, Okumura Y, Hiraki T, Gobara H, Mimura H, Kanazawa S, Kaji M, Fujiwara T

Acta Med Okayama 2011

Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas

Sasaki T, Tazawa H, Hasei J, Kunisada T, Yoshida A, Hashimoto Y, Yano S, Yoshida R, Uno F, Kagawa S, Morimoto Y, Urata Y, Ozaki T, Fujiwara T

Clin Cancer Res 2011

ハイリスク(特に後期高齢者)食道癌症例に対する手術術式の工夫

田辺俊介, 白川靖博, 前田直見, 大原利章, 野間和広, 櫻間教文, 藤原俊義

General Thoracic and Cardiovascular Surgery 59 ( Supplement ) 2011

鉄欠乏マウスモデルを用いた血管新生阻害薬併用療法の基礎的検討

大原利章, 野間和広, 木村文昭, 友野靖子, 西谷正史, 渡辺伸一郎, 藤原俊義

日本鉄バイオサイエンス学会学術集会プログラム・抄録集 35th 2011

放射線療法とPaclitaxel化学療法にて長期CRが得られた胃癌直腸膀胱窩再発の1例

金谷信彦, 香川俊輔, 宇野太, 國富彩, 小川誠之, 藤原俊義

癌と化学療法 38 ( 12 ) 2100 - 2102 2011

センチンネルリンパ節ナビゲーション手術

がん治療レクチャー：新しい手術のモダリティー 2 788 - 792 2011

腹腔鏡補助下噴門側胃切除術；観音開き法食道残胃吻合

消化器外科 34 1687 - 1697 2011

食道癌周術期管理における多職種スタッフ介入の効果

白川靖博, 田辺俊介, 野間和広, 櫻間教文, 山辻知樹, 羽井佐実, 猶本良夫, 伊藤真理, 足羽孝子, 藤原俊義

日外会誌 112 520 - 520 2011

胃がん (新しい手術のモダリティ) -- (最新の外科治療総論 : アプローチを中心に)

西﨑正彦, 香川俊輔, 藤原俊義

がん治療レクチャー : チーム医療のための 2 ( 4 ) 788 - 792 2011

高齢者食道癌症例に対する外科治療の現況と成績

田邊俊介, 白川靖博, 横道直佑, 野間和広, 櫻間教文, 山辻知樹, 羽井佐実, 猶本良夫, 藤原俊義

日本消化器外科学会雑誌(Web) 44 ( Supplement1 ) 2011

食道癌術後患者における基礎代謝量および影響を及ぼす因子の検討

西川みか, 櫻間教文, 栢下淳, 田邊俊介, 野間和広, 白川靖博, 藤原俊義

日本食道学会学術集会プログラム・抄録集 65th 2011

当院消化器外科領域におけるRobotic Surgeryの現状

西崎正彦, 近藤喜太, 田邊俊介, 野間和広, 岸本浩行, 宇野太, 永坂岳司, 香川俊輔, 白川靖弘, 藤原俊義

日本臨床外科学会雑誌 72 2011

まれなBRAF変異-1799-1801(TGA)塩基の欠失(VK600-601E変異)を認めた大腸癌患者の臨床的特徴

母里淑子, 永坂岳司, 藤原俊義

日本臨床腫瘍学会学術集会プログラム・抄録集 9th 2011

遺伝子情報に基づいた大腸がん個別化治療へ : KRAS/BRAF/MSI

永坂岳司, 近藤喜太, 藤原俊義

ファルマシア 46 ( 12 ) 1120 - 1124 2010.12

PRECLINICAL STUDY OF TELOMERASE-SELECTIVE ONCOLYTIC ADENOVIRUS (OBP-301) IN COMBINATION WITH CHEMOTHERAPEUTIC AGENT AND RADIATION

Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Yasuo Urata, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 12 ( 12 ) 1035 - 1036 2010.12

進行膵頭部癌に対する手術治療戦略

横道直佑, 楳田祐三, 松田浩明, 貞森裕, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 杭瀬崇, 八木孝仁, 藤原俊義

日本臨床外科学会雑誌 71 ( 増刊 ) 705 - 705 2010.10

WS-1-7 テロメラーゼ活性を標的とするウイルス製剤の癌診断・治療への応用(癌治療向上のためのtranslational research,ワークショップ(1),第110回日本外科学会定期学術集会)

藤原俊義

日本外科学会雑誌 111 ( 2 ) 157 - 157 2010.3

A Phase I Study of Telomerase-specific Replication Competent Oncolytic Adenovirus (Telomelysin) for Various Solid Tumors

John Nemunaitis, Alex W. Tong, Michael Nemunaitis, Neil Senzer, Anagha P. Phadke, Cynthia Bedell, Ned Adams, Yu-An Zhang, Phillip B. Maples, Salina Chen, Beena Pappen, James Burke, Daiju Ichimaru, Yasuo Urata, Toshiyoshi Fujiwara

MOLECULAR THERAPY 18 ( 2 ) 429 - 434 2010.2

Language：English Publisher：NATURE PUBLISHING GROUP

A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 x 10(10), 1 x 10(11), 1 x 10(12) viral particles). Safety, response and pharmacodynamics were evaluated. Sixteen patients with a variety of solid tumors were enrolled. IT of Telomelysin was well tolerated at all dose levels. Common grade 1 and 2 toxicities included injection site reactions (pain, induration) and systemic reactions (fever, chills). hTERT expression was demonstrated at biopsy in 9 of 12 patients. Viral DNA was transiently detected in plasma in 13 of 16 patients. Viral DNA was detectable in four patients in plasma or sputum at day 7 and 14 post-treatment despite below detectable levels at 24 h, suggesting viral replication. One patient had a partial response of the injected malignant lesion. Seven patients fulfilled Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease at day 56 after treatment. Telomelysin was well tolerated. Evidence of antitumor activity was suggested.

DOI： 10.1038/mt.2009.262

Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination

M. Takakura, M. Nakamura, S. Kyo, M. Hashimoto, N. Mori, T. Ikoma, Y. Mizumoto, T. Fujiwara, Y. Urata, M. Inoue

CANCER GENE THERAPY 17 ( 1 ) 11 - 19 2010.1

Language：English Publisher：NATURE PUBLISHING GROUP

Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01-100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1-10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1- 10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5-1 mu M, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1- 10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg(-1)) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan-Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP. Cancer Gene Therapy (2010) 17, 11-19; doi: 10.1038/cgt.2009.44; published online 7 August 2009

DOI： 10.1038/cgt.2009.44

保存的加療にて軽快した腸管気腫症の一例

藤原裕子, 田邊俊介, 白川靖博, 近藤喜太, 野間和広, 宇野太, 永坂岳司, 香川俊輔, 山辻知樹, 貞森裕, 小林直哉, 藤原俊義, 八木孝仁, 猶本良夫

岡山医学会雑誌 122 ( 2 ) 2010

当院のおける中・下咽頭表在癌に対するESDの工夫

白川靖博, 田邊俊介, 野間和広, 櫻間教文, 山辻知樹, 松岡順治, 高岡宗徳, 河原祥朗, 岡田裕之, 猶本良夫, 藤原俊義

Gastroenterological Endoscopy 52 ( Supplement 2 ) 2010

パラチノースを糖質源とした流動食MHN-01を用いた食道癌周術期栄養管理

山辻知樹, 田邉俊介, 藤原康宏, 藤原康宏, 野間和広, 櫻間教文, 櫻間教文, 高岡宗徳, 白川靖博, 藤原俊義, 木下真一郎, 深澤拓也, 林次郎, 繁光薫, 吉田和弘, 森田一郎, 猶本良夫

日本臨床外科学会雑誌 71 2010

消化管再建法-合併症ゼロへの工夫-I.食道切除後再建法 5.結腸再建

山辻知樹, 白川靖博, 繁光薫, 野間和広, 藤原俊義, 猶本良夫

手術 64 ( 10 ) 2010

当科にて経験した食道GISTの2例

渡邉伸一郎, 白川靖博, 田邊俊介, 野間和広, 櫻間教文, 繁光薫, 山辻知樹, 羽井佐実, 猶本良夫, 藤原俊義

日本食道学会学術集会プログラム・抄録集 64th 2010

食道癌周術期の新しい栄養管理

山辻知樹, 田邊俊介, 野間和広, 櫻間教文, 白川靖博, 藤原俊義, 木下真一郎, 林次郎, 繁光薫, 吉田和弘, 森田一郎, 猶本良夫

岡山医学会雑誌 122 ( 3 ) 2010

小腸間置による胃機能温存食道切除再建術とその臨床的評価

猶本良夫, 山田英司, 田辺俊介, 藤原康宏, 野間和広, 高岡宗徳, 白川靖博, 木下真一郎, 深澤拓也, 繁光薫, 林次郎, 山辻知樹, 吉田和弘, 森田一郎, 藤原俊義

General Thoracic and Cardiovascular Surgery 58 ( Supplement ) 2010

食道原発悪性黒色腫の3例

渡邉伸一郎, 白川靖博, 田辺俊介, 野間和広, 櫻間教文, 繁光薫, 山辻知樹, 羽井佐実, 松岡順治, 猶本良夫, 藤原俊義

General Thoracic and Cardiovascular Surgery 58 ( Supplement ) 2010

当科における回結腸を用いた食道再建術の工夫

白川靖博, 渡邉伸一郎, 田邊俊介, 野間和広, 櫻間教文, 重光薫, 山辻知樹, 羽井佐実, 猶本良夫, 藤原俊義

日本食道学会学術集会プログラム・抄録集 64th 2010

右鎖骨下動脈起始異常と非反回下喉頭神経を伴う食道癌に対する手術経験

田辺俊介, 白川靖博, 二萬英斗, 渡邉伸一郎, 野間和広, 櫻間教文, 繁光薫, 山辻知樹, 羽井佐実, 松岡順治, 猶本良夫, 藤原俊義

General Thoracic and Cardiovascular Surgery 58 ( Supplement ) 2010

当科におけるハイリスク食道癌症例に対する治療方針

白川靖博, 田邊俊介, 藤原康宏, 野間和広, 櫻間教文, 山辻知樹, 貞森裕, 藤原俊義, 八木孝仁, 猶本良夫

日本消化器外科学会雑誌 43 ( Supplement1 (Web) ) 2010

Imatinib耐性GISTに対するSunitinib使用経験

藤原康宏, 田邊俊介, 野間和広, 永坂岳司, 白川靖博, 山辻知樹, 貞森裕, 八木孝仁, 藤原俊義, 猶本良夫

日本消化器外科学会雑誌 43 ( Supplement1 (Web) ) 2010

食道癌再発巣に対する治療方針-PET導入後の治療手段の変遷-

田邊俊介, 藤原康宏, 野間和広, 櫻間教文, 白川靖博, 山辻知樹, 貞森裕, 藤原俊義, 八木孝仁, 猶本良夫

日本消化器外科学会雑誌 43 ( Supplement1 (Web) ) 2010

Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

Oumi Nakajima, Daiju Ichimaru, Yasuo Urata, Toshiyoshi Fujiwara, Tomohisa Horibe, Masayuki Kohno, Koji Kawakami

ONCOLOGY REPORTS 22 ( 5 ) 1039 - 1043 2009.11

Language：English Publisher：SPANDIDOS PUBL LTD

We previously reported that telomerase-specific replication-component adenovirous, Telomelysin (OBP-301) has cytotoxic activity to the YCUT892, KCCT873, KCCT891, KCCL871, YCUM862, HN12, and KCCOR891 cell lines in vitro, and investigated the association between cytotoxic activity and adenoviral receptor expression. In this study, we evaluated the most appropriate way to administer telomelysin (OBP-301) in the treatment of squamous cell carcinoma of the head and neck (SCCHN), and assessed the effect of OBP-301 in large subcutaneous KCCT873 human SCCHN tumors in immunodeficient mice. We also compared antitumor responses following three intratumoral (i.t.) injections of OBP-301 given daily, every 2 days or weekly. To investigate the mechanism of the antitumor effect, we evaluated cellular infiltration in treated tumors. OBP-301 showed remarkable antitumor activity against large KCCT873 tumors, and three treatment schedules produced similar antitumor effects. The weekly regimen also significantly reduced the growth of large tumors. Immunochemistry revealed that macrophages, but not natural killer cells, were responsible for tumor regression. A regimen of three weekly injections of OBP-301 has remarkable antitumor effects against large KCCT873 tumors. These results may provide a new platform for treating patients with localized SCCHN.

DOI： 10.3892/or_00000533

Selective metastatic tumor labeling with green fluorescent protein and killing by systemic administration of telomerase-dependent adenoviruses

Hiroyuki Kishimoto, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara, Robert M. Hoffman

MOLECULAR CANCER THERAPEUTICS 8 ( 11 ) 3001 - 3008 2009.11

Language：English Publisher：AMER ASSOC CANCER RESEARCH

We previously constructed telomerase-dependent, replication-selective adenoviruses OBP-301 (Telomelysin) and OBP-401 [Telomelysin-green fluorescent protein (GFP); TelomeScan], the replication of which is regulated by the human telomerase reverse transcriptase promoter. By intratumoral injection, these viruses could replicate within the primary tumor and subsequent lymph node metastasis. The aim of the present study was to evaluate the possibility of systemic administration of these telomerase-dependent adenoviruses. We assessed the antitumor efficacy of OBP-301 and the ability of OBP-401 to deliver GFP in hepatocellular carcinoma (HCC) and metastatic colon cancer nude mouse models. We showed that i.v. administration of OBP-301 significantly inhibited colon cancer liver metastases and orthotopically implanted HCC. Further, we showed that OBP-401 could visualize liver metastases by tumor-specific expression of the GFP gene after portal venous or i.v. administration. Thus, systemic administration of these adenoviral vectors should have clinical potential to treat and detect liver metastasis and HCC. [Mol Cancer Ther 2009;8(11):3001-8]

DOI： 10.1158/1535-7163.MCT-09-0556

A simple biological imaging system for detecting viable human circulating tumor cells

Toru Kojima, Yuuri Hashimoto, Yuichi Watanabe, Shunsuke Kagawa, Futoshi Uno, Shinji Kuroda, Hiroshi Tazawa, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

JOURNAL OF CLINICAL INVESTIGATION 119 ( 10 ) 3172 - 3181 2009.10

Language：English Publisher：AMER SOC CLINICAL INVESTIGATION INC

The presence of circulating tumor cells (CTCs) in the peripheral blood is associated with short survival, making the detection of CTCs clinically useful as a prognostic factor of disease outcome and/or a surrogate marker of treatment response. Recent technical advances in immunocytometric analysis and quantitative real-time PCR have made it possible to detect a few CTCs in the blood; however, there is no sensitive assay to specifically detect viable CTCs. Here, we report what we believe to be a new approach to visually detect live human CTCs among millions of peripheral blood leukocytes, using a telomerase-specific replication-selective adenovirus expressing GFP. First, we constructed a GFP-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401; TelomeScan). We then used OBP-401 to establish a simple ex vivo method that was able to detect viable human CTCs in the peripheral blood. The detection method involved a 3-step procedure, including the lysis of rbc, the subsequent addition of OBP-401 to the cell pellets, and an automated scan using fluorescence microscopy. OBP-401 infection increased the signal-to-background ratio as a tumor-specific probe, because the fluorescent signal was amplified only in viable, infected human tumor cells, by viral replication. This GFP-expressing virus-based method is remarkably simple and allows precise enumeration of CTCs.

DOI： 10.1172/JCI38609

In vivo internal tumor illumination by telomerase-dependent adenoviral GFP for precise surgical navigation

Hiroyuki Kishimoto, Ming Zhao, Katsuhiro Hayashi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara, Sheldon Penman, Robert M. Hoffman

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 106 ( 34 ) 14514 - 14517 2009.8

Language：English Publisher：NATL ACAD SCIENCES

Cancer surgery requires the complete and precise identification of malignant tissue margins including the smallest disseminated lesions. Internal green fluorescent protein (GFP) fluorescence can intensely illuminate even single cells but requires GFP sequence transcription within the cell. Introducing and selectively activating the GFP gene in malignant tissue in vivo is made possible by the development of OBP-401, a telomerase-dependent, replication-competent adenovirus expressing GFP. This potentially powerful adjunct to surgical navigation was demonstrated in 2 nude mouse models that represent difficult surgical challenges-the resection of widely disseminated cancer. HCT-116, a model of intraperitoneal disseminated human colon cancer, was labeled by virus injection into the peritoneal cavity. A549, a model of pleural dissemination of human lung cancer, was labeled by virus administered into the pleural cavity. Only the malignant tissue fluoresced brightly in both models. In the intraperitoneal model of disseminated cancer, fluorescence-guided surgery enabled resection of all tumor nodules labeled with GFP by OBP-401. The data in this report suggest that adenoviral-GFP labeling tumors in patients can enable fluorescence-guided surgical navigation.

DOI： 10.1073/pnas.0906388106

Diagnostic potential and limitation of imaging cancer cells in cytological samples using telomerase-specific replicative adenovirus

Yoshiko Maida, Satoru Kyo, Junko Sakaguchi, Yasunari Mizumoto, Manabu Hashimoto, Noriko Mori, Tomomi Ikoma, Mitsuhiro Nakamura, Masahiro Takakura, Yasuo Urata, Toshiyoshi Fujiwara, Masaki Inoue

INTERNATIONAL JOURNAL OF ONCOLOGY 34 ( 6 ) 1549 - 1556 2009.6

Language：English Publisher：SPANDIDOS PUBL LTD

Cytological cancer screening that targets genetic or epigenetic abnormalities may be a viable alternative to morphological screening. Detecting cancer cells by specific genetic markers helps their easy detection in cytological samples. We recently established the telomerase-specific replication-selective adenovirus OBP-401, in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted upstream of the El genes, and in which the green fluorescent protein (GFP) gene is driven by the CMV promoter. This virus selectively replicates only in telomerase-positive cells, expressing GFP, and therefore may be a toot for cancer screening. In the present study, we first confirmed that cytological samples can easily be infected with OBP-401, allowing visualization of GFP-positive cells under fluorescent microscopy 24 h after infection. After 32 cytological samples from patients with cervical, endometrial or ovarian cancers were infected with OBP-401, GFP signals were detected in 31 (96%) of the samples. However, some normal endometrial scrapings exhibited GFP-signals, possibly due to endometrial glandular cells with constitutive telomerase activity. The ability of OBP-401 to enrich cancer cells was then tested. Cytological samples containing cervical or endometrial cancer cells were infected with OBP-401, and GFP-positive cells were sorted by flow cytometry; DNA was extracted from the GFP-positive cells. Direct DNA sequencing or methylation-specific PCR identified cancer-derived mutations or hypermethylations of tumor suppressor genes more efficiently than analyses using crude cytological samples. Thus, OBP-401-Z, based sorting of GFP-positive cells successfully enriched cancer cells, allowing efficient detection of genetic or epigenetic abnormalities in cytological samples.

DOI： 10.3892/ijo_00000284

Antiviral activity of cidofovir against telomerase-specific replication-selective oncolytic adenovirus, OBP-301 (Telomelysin)

Masaaki Ouchi, Hitoshi Kawamura, Yasuo Urata, Toshiyoshi Fujiwara

INVESTIGATIONAL NEW DRUGS 27 ( 3 ) 241 - 245 2009.6

Language：English Publisher：SPRINGER

We constructed a replication-competent oncolytic adenovirus, OBP-301 (Telomelysin), in which human telomerase reverse transcriptase (hTERT) promoter drives E1 genes. OBP-301 is currently being used in a phase-I clinical trial for various types of tumors. Under such conditions, anti-adenoviral agents should be available for safety use against OBP-301 since any adenoviral viremia could cause severe adverse effects. Cidofovir (CDV) is an acyclic nucleoside phosphonate that has a broad antiviral activity against DNA viruses. Here, we examined the antiviral effects of CDV against OBP-301. The in vitro cytopathic effects of OBP-301 were suppressed by CDV. Moreover, CDV decreased the adenoviral E1A gene copy number after OBP-301 infection. These results suggest that CDV is a potentially useful antiviral agent for OBP-301.

DOI： 10.1007/s10637-008-9169-5

Preclinical study of telomerase-selective oncolytic adenovirus (OBP-301) in combination with chemotherapeutic agents

Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Yasuo Urata, Toshiyoshi Fujiwara

CANCER RESEARCH 69 2009.5

Preclinical evaluation of telomerase-specific virotheranostics for human head and neck cancer

Yuji Kurihara, Toru Kojima, Tatsuo Shirota, Masashi Hatori, Yasuo Urata, Toshiyoshi Fujiwara, Satoru Shintani

CANCER RESEARCH 69 2009.5

Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer

Dong Liu, Toru Kojima, Masaaki Ouchi, Shinji Kuroda, Yuichi Watanabe, Yuuri Hashimoto, Hideki Onimatsu, Yasuo Urata, Toshiyoshi Fujiwara

MOLECULAR CANCER THERAPEUTICS 8 ( 4 ) 980 - 987 2009.4

Language：English Publisher：AMER ASSOC CANCER RESEARCH

A phase I dose-escalation study of telomerase-specific oncolytic adenovirus, OBP-301 (Telomelysin), is now under way in the United States to assess feasibility and to characterize its pharmacokinetics in patients with advanced solid tumors. The present preclinical study investigates whether OBP-301 and a chemotherapeutic agent that is commonly used for lung cancer treatment, gemcitabine, are able to enhance antitumor effects in vitro and in vivo. The antitumor effects of OBP-301 infection and gemcitabine were evaluated by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt assay. In vivo antitumor effects of intratumoral injection of OBP-301 in combination with systemic administration of gemcitabine were assessed on nu/nu mice s.c. xenografted with human lung tumors. OBP-301 infection combined with gemcitabine resulted in very potent synergistic cytotoxicity in human lung cancer cells. The three human lung cancer cell lines treated with OBP-301 for 24 hours tended to accumulate in S phase compared with controls. The proportion of cells in S phase increased from 43.85% to 56.41% in H460 cells, from 46.72% to 67.09% in H322 cells, and from 38.22% to 57.67% in H358 cells. Intratumoral injection of OBP-301 combined with systemic administration of gemcitabine showed therapeutic synergism in human lung tumor xenografts. Our data suggest that the combination of OBP-301 and gemcitabine enhances the antitumor effects against human lung cancer. We also found that the synergistic mechanism may be due to OBP-301-mediated cell cycle accumulation in S phase. These results have important implications for the treatment of human lung cancer. [Mol Cancer Ther 2009;8(4):980-7]

DOI： 10.1158/1535-7163.MCT-08-0901

Telomerase-Specific Virotheranostics for Human Head and Neck Cancer

Yuji Kurihara, Yuichi Watanabe, Hideki Onimatsu, Toru Kojima, Tatsuo Shirota, Masashi Hatori, Dong Liu, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Satoru Shintani, Toshiyoshi Fujiwara

CLINICAL CANCER RESEARCH 15 ( 7 ) 2335 - 2343 2009.4

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Long-term outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) remain unsatisfactory despite advances in combination of treatment modalities. SCCHN is characterized by locoregional spread and it is clinically accessible, making it an attractive target for intratumoral biological therapies.
Experimental Design: OBP-301 is a type 5 adenovirus that contains the replication cassette in which the human telomerase reverse transcriptase promoter drives expression of the E1 genes. OBP-401 contained the replication cassette and the green fluorescent protein (GFP) gene. The antitumor effects of OBP-301 were evaluated in vitro by the sodium 30-[1-(phenylaminocarbonyl) -3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate assay and in vivo in an orthotopic xenograft model. Virus spread into the lymphatics was also orthotopically assessed by using OBP-401.
Results: Intratumoral injection of OBP-301 resulted in the shrinkage of human SCCHN tumors orthotopically implanted into the tongues of BALB/c nu/nu mice and significantly recovered weight loss by enabling oral ingestion. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Moreover, whole-body fluorescent imaging revealed that intratumorally injected OBP-401 Could visualize the metastatic lymph nodes, indicating the ability of the virus to traffic to the regional lymphatic area and to selectively replicate in neoplastic lesions, resulting in GFP expression and cell death in metastatic lymph nodes.
Conclusions: These results illustrate the potential of telomerase-specific oncolytic viruses for a novel therapeutic and diagnostic approach, termed theranostics, for human SCCHN.

DOI： 10.1158/1078-0432.CCR-08-2690

SY-1-3 テロメラーゼ活性を標的とするウイルス製剤OBP-301の臨床応用 : 固形腫瘍に対する第1相臨床試験(外科領域における遺伝子治療・再生医療の問題点と今後の展開,シンポジウム,第109回日本外科学会定期学術集会)

香川俊輔, 宇野太, 橋本悠里, 浦田泰生, 田中紀章, 藤原俊義

日本外科学会雑誌 110 ( 2 ) 82 - 82 2009.2

Telomerase-specific virotherapy in an animal model of human head and neck cancer

Oumi Nakajima, Atsuko Matsunaga, Daiju Ichimaru, Yasuo Urata, Toshiyoshi Fujiwara, Koji Kawakami

MOLECULAR CANCER THERAPEUTICS 8 ( 1 ) 171 - 177 2009.1

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Telomerase-specific replication-competent adenovirus, Telomelysin (OBP-301), has a human telomerase reverse transcriptase promoter that regulates viral replication and efficiently kills human cancer cells. The objectives of this study are to examine the effects of OBP-301 in squamous cell carcinoma of the head and neck cells in vitro and in xenografted animals in vivo. OBP-301 was found to be cytotoxic to the YCUT892, KCCT873, KCCT891, KCCL871, YCUM862, HN12, and KCCOR891 cell lines in vitro. However, the level of cytotoxicity is not correlated with the expression levels of adenoviral receptors, which may be required for adenoviral infection in squamous cell carcinoma of the head and neck cells. OBP-301 shows remarkable antitumor activity against established s.c. KCCT873 tumors in immunodeficient animals in a dose-dependent manner. In addition, no significant toxicity was observed in animals receiving treatment. These results suggest that OBP-301 is a novel therapeutic agent with promise for the treatment of human head and neck cancers. [Mol Cancer Ther 2009(1): 171 - 7]

DOI： 10.1158/1535-7163.MCT-08-0620

Gene therapy and virotherapy for human cancer

Japanese journal of clinical medicine 67 306 - 313 2009.1

A novel antiangiogenic effect for telomerase-specific virotherapy through host immune system

Ikeda Y, Kojima T, Kuroda S, Endo Y, Sakai R, Hioki M, Kishimoto H, Uno F, Kagawa S, Watanabe Y, Hashimoto Y, Urata Y, Tanaka N, Fujiwara T

J Immunol 182 1763 - 1769 2009

RFA前のPET/CTにおけるSUVとRFA後の腫瘍再発との関連性について

原田聡介, 奥村能啓, 郷原英夫, 平木隆夫, 加藤勝也, 佐藤修平, 三村秀文, 丸中三菜子, 佐野由文, 藤原俊義, 加地充昌, 金澤右

肺癌 49 ( 5 ) 2009

肺癌RFA3,6カ月後のPET/CTの集積程度の検討

奥村能啓, 郷原英夫, 井上大作, 平木隆夫, 三村秀文, 金澤右, 佐野由文, 藤原俊義, 加地充昌

IVR 24 ( 4 ) 2009

Autophagy-inducing agents augment the antitumor effect of telomerase-selective oncolytic adenovirus OBP-405 on glioblastoma cells

T. Yokoyama, E. Iwado, Y. Kondo, H. Aoki, Y. Hayashi, M. M. Georgescu, R. Sawaya, K. R. Hess, G. B. Mills, H. Kawamura, Y. Hashimoto, Y. Urata, T. Fujiwara, S. Kondo

GENE THERAPY 15 ( 17 ) 1233 - 1239 2008.9

Language：English Publisher：NATURE PUBLISHING GROUP

Oncolytic adenoviruses are a promising tool in cancer therapy. In this study, we characterized the role of autophagy in oncolytic adenovirus-induced therapeutic effects. OBP-405, an oncolytic adenovirus regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD) exhibited a strong antitumor effect on glioblastoma cells. When autophagy was inhibited pharmacologically, the cytotoxicity of OBP-405 was attenuated. In addition, autophagy-deficient Atg5 mouse embryonic fibroblasts (MEFs) were less sensitive than wild-type MEFs to OBP-405. These findings indicate that OBP-405-induced autophagy is a cell killing effect. Moreover, autophagy-inducing therapies (temozolomide and rapamycin) synergistically sensitized tumor cells to OBP-405 by stimulating the autophagic pathway without altering OBP-405 replication. Mice harboring intracranial tumors treated with OBP-405 and temozolomide survived significantly longer than those treated with temozolomide alone, and mice treated with OBP-405 and the rapamycin analog RAD001 survived significantly longer than those treated with RAD001 alone. The observation that autophagy inducers increase OBP-405 antitumor activity suggests a novel strategy for treating patients with glioblastoma.

DOI： 10.1038/gt.2008.98

Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers

Satoru Kyo, Masahiro Takakura, Toshiyoshi Fujiwara, Masaki Inoue

CANCER SCIENCE 99 ( 8 ) 1528 - 1538 2008.8

Language：English Publishing type：Book review, literature introduction, etc. Publisher：WILEY-BLACKWELL

Telomerase activation is a critical step for human carcinogenesis through the maintenance of telomeres, but the activation mechanism during carcinogenesis remains unclear. Transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is the major mechanism for cancer-specific activation of telomerase, and a number of factors have been identified to directly or indirectly regulate the hTERT promoter, including cellular transcriptional activators (c-Myc, Sp1, HIF-1, AP2, ER, Ets, etc.) as well as the repressors, most of which comprise tumor suppressor gene products, such as p53, WT1, and Menin. Nevertheless, none of them can clearly account for the cancer specificity of hTERT expression. The chromatin structure via the DNA methylation or modulation of nucleosome histones has recently been suggested to be important for regulation of the hTERT promoter. DNA unmethylation or histone methylation around the transcription start site of the hTERT promoter triggers the recruitment of histone acetyltransferase (HAT) activity, allowing hTERT transcription. These facts prompted us to apply these regulatory mechanisms to cancer diagnostics and therapeutics. Telomerase-specific replicative adenovirus (Telomelysin, OBP-301), in which E1A and E1B genes are driven by the hTERT promoter, has been developed as an oncolytic virus that replicates specifically in cancer cells and causes cell death via viral toxicity. Direct administration of Telomelysin was proved to effectively eradicate solid tumors in vivo, without apparent adverse effects. Clinical trials using Telomelysin for cancer patients with progressive stages are currently ongoing. Furthermore, we incorporated green fluorescent protein gene (GFP) into Telomelysin (TelomeScan, OBP-401). Administration of TelomeScan into the primary tumor enabled the visualization of cancer cells under the cooled charged-coupled device (CCD) camera, not only in primary tumors but also the metastatic foci. This technology can be applied to intraoperative imaging of metastatic lymphnodes. Thus, we found novel tools for cancer diagnostics and therapeutics by utilizing the hTERT promoter. (Cancer Sci 2008; 99: 1528-1538)

DOI： 10.1111/j.1349-7006.2008.00878.x

Combination of oncolytic adenovirotherapy and Bax gene therapy in human cancer xenografted models. Potential merits and hurdles for combination therapy

Masayoshi Hioki, Shunsuke Kagawa, Toshiya Fujiwara, Ryo Sakai, Turn Kojima, Yuichi Watanabe, Yuuri Hashimoto, Futoshi Uno, Norialki Tanaka, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 122 ( 11 ) 2628 - 2633 2008.6

Language：English Publisher：WILEY-LISS

Cancer gene therapy and oncolytic virotherapy have been studied extensively. However, their clinical application is hampered by their weak anticancer activity. We previously constructed a replicating adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of the adenoviral El genes, and causes selective lysis of human cancer cells. We hypothesized that combination adenoviral therapy containing OBP-301 and a nonreplicating adenovirus expressing the proapoptotic Bax gene could overcome the weakness and augment the anticancer efficacy of each modality. Combination treatment resulted in marked Bax protein expression and enhanced efficacy in in vitro cell viability assay, when compared with either single treatment. However, combination treatment was not as effective in suppressing both subcutaneous and pleural disseminated tumors compared with OBP-301 treatment alone. Further investigation revealed that combination treatment resulted in suppressed EIA protein expression associated with reduced viral replication. Our results suggest that Bax gene therapy in combination with oncolytic adenovirotherapy potentially augments their antitumor activity, but further improvements may be required to maximize the combinatorial effect in vivo, for the Bax gene expression to avoid interference with production of the oncolytic virus. (c) 2008 Wiley-Liss, Inc.

DOI： 10.1002/ijc.23438

Direct and distant antitumor effects of a telomerase-selective oncolytic adenoviral agent, OBP-301, in a mouse prostate cancer model

P. Huang, M. Watanabe, H. Kaku, Y. Kashiwakura, J. Chen, T. Saika, Y. Nasu, T. Fujiwara, Y. Urata, H. Kumon

CANCER GENE THERAPY 15 ( 5 ) 315 - 322 2008.5

Language：English Publisher：NATURE PUBLISHING GROUP

We previously constructed OBP-301 ( Telomelysin, a telomerase-specific replication-competent adenovirus with human telomerase reverse transcriptase ( hTERT) promoter), which showed a strong anticancer effect by inducing cell lysis of human non-small cell lung cancer and colorectal cancer cells. To investigate the utility of OBP-301 for prostate cancer treatment, we herein evaluate the cell killing and antitumor effects. First, in vitro hTERT-specific adenovirus transduction in human prostate cancer cells ( LNCaP, PC3, DU145) was confirmed using OBP-401 ( Telomelysin-green fluorescent protein ( GFP)). There was no detectable GFP transduction in the human prostate normal cells ( PrEC, PrSC). Consistently, the cell-killing effect of OBP-301 was observed only in the cancer cells. Second, using an in vivo subcutaneous LNCaP tumor model in nude mice, we demonstrated that three intratumoral OBP-301 injections ( 10(7) PFU per tumor x 3 days) were sufficient to eradicate the detectable LNCaP prostate tumor. We also demonstrated that the ispilateral treatment with OBP-301 significantly suppressed contralateral LNCaP tumor growth in both sides of the tumor model. Histological and immunohistochemical analyses revealed diffuse oncolytic degeneration and adenoviral E1A protein expression in both sides of the tumors. Therefore, in situ OBP-301 administration could be a promising therapeutic strategy against prostate cancer and its metastatic lesions.

DOI： 10.1038/cgt.2008.3

DP-141-5 当科における食道癌術後深部静脈血栓症の発症要因とリスク解析(第108回日本外科学会定期学術集会)

山辻知樹, 猶本良夫, 田邊俊介, 藤原康弘, 渡辺信之, 櫻間一史, 伊藤充矢, 西川敏雄, 元木崇之, 田渕陽子, 高岡宗徳, 白川靖博, 小林直哉, 藤原俊義, 松原長秀, 平松聡, 羽井佐実, 松岡順治, 田中紀章

日本外科学会雑誌 109 ( 2 ) 626 - 626 2008.4

WS-4-1 テロメラーゼ活性を標的とした新規ウイルス製剤Telomelysin/TelomeScanの癌診断・治療への応用(第108回日本外科学会定期学術集会)

藤原俊義, 香川俊輔, 宇野太, 浦田泰生, 田中紀章

日本外科学会雑誌 109 ( 2 ) 146 - 146 2008.4

DP-086-2 食道癌術前診断におけるPET/CTの有用性についての検討(第108回日本外科学会定期学術集会)

田辺俊介, 猶本良夫, 藤原康宏, 櫻間一史, 野間和広, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 羽井佐実, 松岡順治, 田中紀章

日本外科学会雑誌 109 ( 2 ) 516 - 516 2008.4

Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation

Y. Endo, R. Sakai, M. Ouchi, H. Onimatsu, M. Hioki, S. Kagawa, F. Uno, Y. Watanabe, Y. Urata, N. Tanaka, T. Fujiwara

ONCOGENE 27 ( 17 ) 2375 - 2381 2008.4

Language：English Publisher：NATURE PUBLISHING GROUP

Dendritic cells ( DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell- to- cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP- 301 ( Telomelysin) is a telomerase-specific replication- competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP- 301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-gamma ( IFN-gamma) and interleukin 12 ( IL- 12). Subsequently, IFN-gamma release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T- lymphocytes. Our data suggest that virus- mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.

DOI： 10.1038/sj.onc.1210884

Establishment of biological and pharmacokinetic assays of telomerase-specific replication-selective adenovirus

Yuuri Hashimoto, Yuichi Watanabe, Yoshiko Shirakiya, Futoshi Uno, Shunsuke Kagawa, Hitoshi Kawamura, Katsuyuki Nagai, Noriaki Tanaka, Horomi Kumon, Yasuo Urata, Toshiyoshi Fujiwara

CANCER SCIENCE 99 ( 2 ) 385 - 390 2008.2

Language：English Publisher：BLACKWELL PUBLISHING

The use of replication-selective tumor-specific viruses represents a novel approach for the treatment of neoplastic disease. We constructed an attenuated adenovirus, telomerase-specific replication-selective adenovirus (TRAD), in which the human telomerase reverse transcriptase promoter element drives the expression of the E1A and E1B genes linked with an internal ribosome entry site (IRES). Forty-eight hours after TRAD infection at a multiplicity of infection of 1.0, the cell viability of H1299 human lung cancer cells was consistently less than 50% and therefore this procedure could be used as a potency assay to assess the biological activity of TRAD. We also established a quantitative real-time polymerase chain reaction (PCR) analysis with consensus primers for either the adenovirus E1A or IRES sequence. The linear ranges of quantitation with E1A and IRES primers were 10(3)-10(8) and 10(2)-10(8) plaque-forming units/mL in the plasma, respectively. The PCR analysis demonstrated that the levels of E1A in normal tissues were more than 10(3) lower than in the tumors of A549 human lung tumor xenografts in nu/n mu mice at 28 days after intratumoral injection. Our results suggest that the cell-killing assay against H1299 cells and real-time PCR can be used to assess the biological activity and biodistribution of TRAD in clinical trials.

DOI： 10.1111/j.1349-7006.2007.00665.x

Diagnostic and therapeutic application of telomerase-specific oncolytic adenoviral agents

Toshiyoshi Fujiwara, Yasuo Urata, Noriaki Tanaka

FRONTIERS IN BIOSCIENCE-LANDMARK 13 1881 - 1886 2008.1

Language：English Publisher：FRONTIERS IN BIOSCIENCE INC

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site (IRES). Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. We further modified the E3 region of OBP-301 to contain green fluorescent protein (GFP) gene for monitoring viral replication (TelomeScan, OBP-401). When TelomeScan was intratumorally injected into human tumors orthotopically implanted into the rectum in mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that TelomeScan causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This article reviews recent highlights in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the telomerase-specific oncolytic adenoviruses.

DOI： 10.2741/2807

微小癌転移のin vivoイメージング技術.

藤原俊義, 田中紀章

Medical Science Digest 34 ( 2 ) 48 - 49 2008

腫瘍融解ウイルスによる細胞死であるオンコライシスは細胞内にdanger signalを発生させ、プロテアソームアクチベーター（PA28）発現を増強することで細胞障害性Tリンパ球による免疫応答を活性化する.

遠藤芳克, 酒井亮, 大内正明, 鬼松秀樹, 日置勝義, 香川俊輔, 宇野太, 渡邉雄一, 浦田泰生, 田中紀章, 藤原俊義

岡山医学会雑誌 120 ( 3 ) 259 - 264 2008

テロメラーゼ活性を標的とした腫瘍融解ウイルスのがん診断・治療への応用.

藤原俊義, 田中紀章

Cancer Frontier 10 ( 1 ) 49 - 56 2008

遺伝子治療.

藤原俊義, 田中紀章

日本臨床 66 ( Suppl 6 ) 173 - 179 2008

ウイルスによる細胞死とがん治療への応用.

藤原俊義, 田中紀章

がん分子標的治療 6 ( 3 ) 152 - 159 2008

がんに対する遺伝子治療の現況と展望.

藤原俊義, 田中紀章

岡山医学会雑誌 120 ( 3 ) 321 - 327 2008

Telomerase-Specific Oncolytic Virotherapy for Human Cancer with the hTERT Promoter

FUJIWARA Toshiyoshi, TANAKA Noriaki

Uirusu 58 ( 1 ) 11 - 18 2008

Language：Japanese Publisher：The Japanese Society for Virology

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. We further modified the E3 region of OBP-301 to contain green fluorescent protein (GFP) gene for monitoring viral replication (TelomeScan, OBP-401). When TelomeScan was intratumorally injected into human tumors orthotopically implanted into the rectum in mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. This article reviews recent highlights in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the telomerase-specific oncolytic adenoviruses.

DOI： 10.2222/jsv.58.11

Other Link： https://jlc.jst.go.jp/DN/JALC/00323509631?from=CiNii

In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus

KISHIMOTO Hiroyuki, KOJIMA Toru, WATANABE Yuichi, KAGAWA Shunsuke, FUJIWARA Toshiya, UNO Futoshi, TERAISHI Fuminori, KYO Satoru, MIZUGUCHI Hiroyuki, HASHIMOTO Yuuri, URATA Yasuo, TANAKA Noriaki, FUJIWARA Toshiyoshi

120 ( 1 ) 13 - 21 2008

制限増殖型アデノウイルス製剤を用いた、消化器癌微小リンパ節転移の診断、および治療への応用.

児島亨, 田中紀章, 浦田泰生, 藤原俊義

癌の臨床 54 ( 3 ) 163 - 168 2008

微小リンパ節転移を標的とするテロメラーゼ特異的腫瘍融解ナノバイオウイルス製剤によるイメージングシステムおよび治療法の開発.

児島亨, 田中紀章, 浦田泰生, 藤原俊義

Biotherapy 22 ( 2 ) 87 - 95 2008

PET/CTによる肺癌RFA後の再発診断の至適時期の検討

奥村能啓, 郷原英夫, 井上大作, 平木隆夫, 三村秀文, 佐藤修平, 加藤勝也, 加地充昌, 佐野由文, 藤原俊義, 金澤右

肺癌 48 ( 5 ) 2008

当科における食道切除後,遺残食道癌症例の検討

野間和広, 猶本良夫, 藤智和, 田邊俊介, 近藤喜太, 藤原康宏, 吉田亮介, 櫻間一史, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 120 ( 2 ) 2008

当科における食道切除後,再建胃管癌症例の検討

田邊俊介, 猶本良夫, 藤智和, 近藤喜太, 藤原康宏, 吉田亮介, 野間和広, 櫻間一史, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 120 ( 2 ) 2008

Adenomyoma of the stomach presenting as localized peritonitis

Shunsuke Kagawa, Toshiyoshi Fujiwara, Masahiko Nishizaki, Yoshio Naomoto, Isozaki Hiroshi, Noriaki Tanaka

DIGESTIVE DISEASES AND SCIENCES 52 ( 11 ) 3184 - 3187 2007.11

Knock down of hSNF5/Ini1 causes cell cycle arrest and apoptosis in a p53-dependent manner

Hiroyuki Kato, Reiko Honma, Takaomi Sanda, Toshiyoshi Fujiwara, Emi Ito, Yuka Yanagisawa, Jun-ichi Imai, Takashi Okamoto, Shinya Watanabe

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 361 ( 3 ) 580 - 585 2007.9

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

hSNF5/Inil is a core component of the SWI/SNF complex and the gene is frequently mutated in aggressive pediatric rhabdoid tumors. Mechanisms of the malignant transformation, however, remain poorly understood. We analyzed HeLa cells treated with siRNA to the hSNF5/Inil mRNA. The resulting efficient and long-term suppression caused characteristic cell enlargement, cell cycle arrest in G1 phase, and subsequent modest apoptosis. Gene expression profiling of the hSNF5-down-regulated cells by cDNA microarray analysis revealed that a limited number of p53-responsive genes, especially p21, were up-regulated. The p53 protein level was also greatly enhanced, suggesting that loss of hSNF5/Inil induces a p53 signaling pathway irrelevant to the chk1/2 phosphorylation pathway. Some rhabdoid tumors with very low or no ARF expression were induced to undergo cell enlargement, growth arrest, and, in one case, apoptosis by ectopic expression of the p14ARF protein. These results may in part account for molecular mechanisms of rhabdoid tumor formation. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.07.035

Clonality and heterogeneity of pulmonary blastoma from the viewpoint of genetic alterations: A case report

Kenji Takahashi, Takashi Kohno, Shingo Matsumoto, Yukihiro Nakanishi, Yasuhito Arai, Toshiyoshi Fujiwara, Noriaki Tanaka, Jun Yokota

LUNG CANCER 57 ( 1 ) 103 - 108 2007.7

Language：English Publisher：ELSEVIER IRELAND LTD

Biphasic pulmonary blastoma is a rare lung tumor with epithelia[ and mesenchymal components. Genetic alterations in this tumor are largely unknown, except for the presence of beta-catenin and p53 mutations and the absence of KRAS mutation. To understand the molecular process of histogenesis of this tumor, a whole genome allelic imbalance (Al) scanning using a high-resolution single nucleotide polymorphism array as well as mutational analysis of the p53, EGFR, KRAS and beta-catenin genes were performed against the epithelial and mesenchymal components in the primary tumor and a metastatic tumor in a case of pulmonary blastoma. Al at chromosome regions 14q24-q32 and 17p11-p13 and beta-catenin mutation were commonly detected in all tumors. On the other hand, Al at chromosome regions 3p11-p14 and 9p21-p24 and p53 mutation were detected only in the mesenchymal component in the primary tumor but not in the epithelial component in the primary tumor and the brain metastasis. Likewise, Al at chromosome regions 6p24-p25 and 6q14-q27 was detected in the epithelial. component in the primary tumor and the brain metastasis but not in the mesenchymal component in the primary tumor. Furthermore, the genetic alterations detected in the metastatic tumor were completely the same as those in the epithelial component in the primary tumor, indicating that a tumor cell(s) in the epithelial component in the primary tumor selectively metastasized to the brain. These results indicate that this biphasic tumor is of monoclonal origin and the phenotypic heterogeneity of the tumor is due to the differences in the accumulated genetic alterations in each component of the tumor. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2007.01.026

Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients

Yuji Sato, Toshiyoshi Fujiwara, Takashi Mine, Hiroki Shomura, Shigenori Homma, Yoshiaki Maeda, Naoyuki Tokunaga, Yoshihiro Ikeda, Yuki Ishihara, Akira Yamada, Noriaki Tanaka, Kyogo Itoh, Mamoru Harada, Satoru Todo

CANCER SCIENCE 98 ( 7 ) 1113 - 1119 2007.7

Language：English Publisher：BLACKWELL PUBLISHING

The aim of the present study was to investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of a 5-fluorouracil derivative (TS-1) in advanced gastric or colorectal carcinoma patients. Eleven patients (four with gastric cancer and seven with colorectal cancer) who failed to improve by prior TS-1-based chemotherapies were enrolled in this study. Peptides to be administered to patients were determined based on the presence of peptide-specific cytotoxic T lymphocyte (CTL) precursors in peripheral blood mononuclear cells and peptide-specific IgG in the plasma of cancer patients. Patients were vaccinated with peptides (a maximum of four) biweekly in combination with or without three different doses of TS-1 (20, 40 and 80 mg/m(2)/day). Although grade 3 toxicity, including anemia (one patient) and neutropenia (one patient) were observed, the combination therapy was generally well tolerated. An increase in peptide-specific IgG after the sixth vaccination was observed in the vast majority of patients irrespective of the dose of TS-1 used. In contrast, an increase in peptide-specific interferon-gamma production by CTL was most evident in patients who were administered the highest dose of TS-1. Furthermore, in the patients who received 80 mg/m(2)/day TS-1, CTL-mediated cytotoxicity against cancer cells was maintained at the prevaccination level. These results indicate that administration of the standard dose (80 mg/m(2)/day) of TS-1 in combination with a personalized peptide vaccination does not necessarily impede immunological responses in cancer patients, and could actually maintain or augment them.

DOI： 10.1111/j.1349-7006.2007.00498.x

Effects of a novel palatinose based enteral formula (MHN-01) carbohydrate-adjusted fluid diet in improving the metabolism of carbohydrates and lipids in patients with esophageal cancer complicated by diabetes mellitus

Toshiya Fujiwara, Yoshio Naomoto, Takayuki Motoki, Kaori Shigemitsu, Yasuhiro Shirakawa, Tomoki Yamatsuji, Masafumi Kataoka, Minoru Haisa, Toshiyoshi Fujiwara, Maritoki Egi, Hiroshi Morimatsu, Motohiko Hanazaki, Hiroshi Katayama, Kiyoshi Morita, Kenji Mizumoto, Takanobu Asou, Hirofumi Arima, Hajime Sasaki, Motoi Matsuura, Mehmet Gunduz, Noriaki Tanaka

JOURNAL OF SURGICAL RESEARCH 138 ( 2 ) 231 - 240 2007.4

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Background. During perioperative management of patients with gastrointestinal cancer complicated by diabetes mellitus, adequate alimentation is required, but we often face difficulties associated with hyperglycemia and other accompanying complications. Recently, we investigated the effects of a novel palatinose based enteral formula (MHN-01) in suppressing post-prandial hyperglycemia and improving lipid metabolism in experimental animals and perioperative management of patients with esophageal cancer complicated by diabetes mellitus.
Materials and methods. We gave normal rats and rats with type 2 diabetes mellitus a single oral dose of fluid diet, and analyzed comparatively the time course of blood glucose level in each group until 3 h after the dose. In both the normal rat group and the type 2 diabetes group, peak blood glucose level after the MHN-01 dose was significantly lower than after a dose of ordinary fluid diet and was comparable to the peak level after a dose of a fluid diet rich in MUFA (monounsaturated fatty acid). We allowed normal mice free access to fluid diet for 43 days, and measured their body fat levels. Fat accumulation was significantly lower in mice given MHN-01 than in mice given ordinary fluid diet. We also analyzed the respiratory quotient and resting energy expenditure of normal Sprague-Dawley rats fed by MHN-01 or an ordinary fluid diet. The respiratory quotient of the MHN-01 group was significantly lower than the ordinary fluid group, although the resting energy expenditure of both groups was almost the same level. The effect of MHN-01 was estimated to be based on improvement of lipid metabolism.
Results. Between 2003 and 2005, among 164 patients who underwent radical thoracic esophagectomy and/or reconstruction for esophageal carcinoma at Okayama University Hospital, nine patients (5.5%) were diagnosed with diabetes mellitus in preoperative screening and were treated with MHN-01. Clinical courses of two cases with severe status of diabetes mellitus were presented as successful case reports of MHN-01.
Conclusion. MHN-01 was very useful in perioperative management of patients complicated by diabetes mellitus, unable to ingest food p.o. such as esophageal cancer or other diseases. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jss.2006.06.025

DP-139-6 切除不能gastrointestinalstromaltumor(GIST)に対する制限増殖型アデノウイルス(Telome-lysin)を用いた新規癌ウイルス療法の確立(第107回日本外科学会定期学術集会)

寺石文則, 橋本悠里, 児島亨, 宇野太, 香川俊輔, 合地明, 田中紀章, 藤原俊義

日本外科学会雑誌 108 ( 2 ) 598 - 598 2007.3

DP-190-6 食道癌周術期管理におけるCTの有用性の検討(第107回日本外科学会定期学術集会)

藤原康宏, 猶本良夫, 田辺俊介, 櫻間一史, 高岡宗徳, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 羽井佐実, 岩垣博巳, 松岡順治, 田中紀章

日本外科学会雑誌 108 ( 2 ) 700 - 700 2007.3

胃癌腹膜播種に対するTRAIL発現 oncolytic adenovirus の抗腫瘍効果

香川俊輔, 日置勝義, 池田義博, 児島亨, 酒井亮, 宇野太, 寺石文則, 橋本悠里, 浦田泰生, 田中紀章, 藤原俊義

日本外科学会雑誌 108 310 - 310 2007.3

DP-190-1 パラチノースを主糖質源とした調整流動食MHN-01(Inslow)の糖質脂質代謝改善効果 : 糖尿病合併食道癌周術期栄養管理への応用(第107回日本外科学会定期学術集会)

山辻知樹, 猶本良夫, 藤原俊哉, 田辺俊介, 藤原康宏, 元木崇之, 渡辺信之, 櫻間一史, 田淵陽子, 大多和泰幸, 鴨宣之, 西川敏雄, 高岡宗徳, 伊藤充矢, 白川靖博, 藤原俊義, 松原長秀, 岩垣博巳, 松剛順治, 羽井佐実, 田中紀章

日本外科学会雑誌 108 ( 2 ) 699 - 699 2007.3

DP-180-4 食道癌放射線化学療法施行後に発症した骨髄異形成症候群の検討(第107回日本外科学会定期学術集会)

田辺俊介, 猶本良夫, 藤原康宏, 櫻間一史, 高岡宗徳, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 羽井佐実, 岩垣博巳, 松岡順治, 田中紀章

日本外科学会雑誌 108 ( 2 ) 679 - 679 2007.3

消化器癌の微小リンパ節転移を標的とする新規ウイルス製剤OBP-301による治療法の開発

児島亨, 藤原俊義, 渡辺雄一, 橋本悠里, 酒井亮, 黒田新士, 浦田泰生, 宇野太, 香川俊輔, 田中紀章

日本外科学会雑誌 108 77 - 77 2007.3

Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter

Toshiyoshi Fujiwara, Yasuo Urata, Noriaki Tanaka

CURRENT CANCER DRUG TARGETS 7 ( 2 ) 191 - 201 2007.3

Language：English Publishing type：Book review, literature introduction, etc. Publisher：BENTHAM SCIENCE PUBL LTD

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. For targeting cancer cells, there is a need for tissue- or cell-specific promoters that can express in diverse tumor types and are silent in normal cells. Recent advances in molecular biology have fostered remarkable insights into the molecular basis of neoplasm. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication. We constructed an attenuated adenovirus 5 vector (Telotnelysin, OBP-301), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site (IRES). Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. Thus, the hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. This article reviews recent findings in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the hTERT promoter.

DOI： 10.2174/156800907780058835

Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter

Toshiyoshi Fujiwara, Yasuo Urata, Noriaki Tanaka

Current Cancer Drug Targets 7 ( 2 ) 191 - 201 2007.3

Language：English Publishing type：Book review, literature introduction, etc.

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. For targeting cancer cells, there is a need for tissue- or cell-specific promoters that can express in diverse tumor types and are silent in normal cells. Recent advances in molecular biology have fostered remarkable insights into the molecular basis of neoplasm. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site (IRES). Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. Thus, the hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. This article reviews recent findings in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the hTERT promoter. © 2007 Bentham Science Publishers Ltd.

DOI： 10.2174/156800907780058835

Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells

Kenji Takahashi, Takashi Kohno, Shingo Matsumoto, Yukihiro Nakanishi, Yasuhito Arai, Seiichiro Yamamoto, Toshiyoshi Fujiwara, Noriaki Tanaka, Jun Yokota

CLINICAL CANCER RESEARCH 13 ( 1 ) 111 - 120 2007.1

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Several models of cancer progression, including clonal evolution, parallel evolution, and same-gene models, have been proposed to date. The purpose of this study is to investigate the authenticity of these models by comparison of accumulated genetic alterations between primary and corresponding metastatic lung cancers.
Experimental Design: A whole-genome allelic imbalance scanning using a high-resolution single nucleotide polymorphism array and mutational analysis of the p53, EGFR, and KRAS genes were done on eight sets of primary and metastatic lung cancers. Based on the genotype data, the natural history of each case was deduced, and candidate metastasis suppressor loci were determined.
Results: Five to 20 chromosomal regions showed allelic imbalance in each tumor. Accumulated genetic alterations were similar between primary and corresponding metastatic tumors, and the majority (>67%) of genetic alterations detected in metastatic tumors was also detected in the corresponding primary tumors. On the other hand, in seven of the eight cases, there were genetic alterations accumulated only in metastatic tumors. Among these alterations, allelic imbalances at chromosome 11p15 and 11p11-p13 regions were the most frequent ones (4 of 8, 50%). Likewise, four cases showed genetic alterations detected only In primary tumors.
Conclusions: The natural history of each case indicated that the process of metastasis varies among cases, and that all three models are applicable to lung cancer progression. According to the clonal and parallel evolution models, it is possible that a metastasis suppressor gene(s) for lung cancer is present on chromosome 11p.

DOI： 10.1158/1078-0432.CCR-06-0659

Cisplatin/Docetaxel+同時性放射線照射が奏効し根治手術を施行し得たstage IIIA非小細胞肺癌の1例

寺石文則, 香川俊輔, 宇野太, 武田洋正, 瀧川奈義夫, 藤原俊義, 田中紀章

癌と化学療法 34 ( 9 ) 1493 - 1495 2007

A case of nodular silicosis mimicking metastatic lung tumors

62 ( 9 ) 1269 - 1271 2007

Focal GGO病変に対するCTガイド下肺生検についての検討

井上大作, 郷原英夫, 三村秀文, 加藤勝也, 平木隆夫, 藤原寛康, 田尻展久, 金澤右, 藤原俊義, 佐野由文, 伊達洋至

肺癌 47 ( 5 ) 2007

テロメラーゼ特異的ウイルス製剤の癌診断・治療への応用.

藤原俊義, 田中紀章

ゲノム医学 7 ( 2 ) 129 - 134 2007

GFP発現ウイルス製剤を用いた消化器癌微小転移のin vivoイメージングシステム.

藤原俊義, 田中紀章

医学のあゆみ 220 ( 8 ) 659 - 661 2007

Theranostic application of telomerase-specific oncolytic adenovirus for human cancer

Japanese journal of clinical medicine 65 ( 10 ) 1913 - 1922 2007

「腫瘍外科治療の最前線」癌のウイルス療法.

藤原俊義, 田中紀章

外科治療 96 ( Suppl ) 368 - 373 2007

Adenoviral p53 Gene Therapy for Lung Cancer

Fujiwara Toshiyoshi, Tanaka Noriaki

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 119 ( 3 ) 229?234 - 234 2007

Language：Japanese Publisher：Okayama Medical Association

To determine the feasibility, safety, humoral immune response, and biological activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small cell lung cancer (NSCLC). Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled into this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 × 10⁹ to 1 × 10¹¹ plaque-forming units[PFU]) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m²). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing anti-adenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting ≥9 months, and 2 patients had progressive disease. Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

DOI： 10.4044/joma.119.229

Other Link： http://ousar.lib.okayama-u.ac.jp/13215

ナノバイオ・ウイルス製剤のがん診断への応用.

藤原俊義

Medical Bio 4 ( 7 ) 39 - 43 2007

O-8 テロメラーゼ活性を標的とした新規腫瘍融解ウイルスによる悪性胸膜中皮腫の診断と治療(中皮腫, 第47回日本肺癌学会総会)

藤原俊義, 渡辺雄一, 橋本悠里, 香川俊輔, 宇野太, 寺石文則, 浦田泰生, 田中紀章

肺癌 46 ( 5 ) 488 - 488 2006.11

In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus

Hiroyuki Kishimoto, Toru Kojima, Yuichi Watanabe, Shunsuke Kagawa, Toshiya Fujiwara, Futoshi Uno, Fuminori Teraishi, Satoru Kyo, Hiroyuki Mizuguchi, Yuuri Hashimoto, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

NATURE MEDICINE 12 ( 10 ) 1213 - 1219 2006.10

Language：English Publisher：NATURE PUBLISHING GROUP

Currently available methods for detection of tumors in vivo such as computed tomography and magnetic resonance imaging are not specific for tumors. Here we describe a new approach for visualizing tumors whose fluorescence can be detected using telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains the replication cassette, in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes, and the GFP gene for monitoring viral replication. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that OBP-401 causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This technology is adaptable to detect lymph node metastasis in vivo as a preclinical model of surgical navigation.

DOI： 10.1038/nm1404

Esophageal intramural pseudodiverticulosis with esophageal strictures successfully treated with dilation therapy

Fuminori Teraishi, Toshiyoshi Fujiwara, Atsushi Jikuhara, Shingo Kamitani, Yasuo Morino, Katsuaki Sato, Noriaki Tanaka

ANNALS OF THORACIC SURGERY 82 ( 3 ) 1119 - 1121 2006.9

Language：English Publisher：ELSEVIER SCIENCE INC

We report a rare case of esophageal intramural pseudodiverticulosis with esophageal strictures. Barium esophagogram demonstrated multiple flask-shaped diverticula out of the esophageal wall with comprehensive luminal stenosis involving the proximal 8 cm and distal 4 cm of the esophagus. Chest computed tomographic scan demonstrated round wall thickening and several intramural gas collections of the proximal esophagus. Endoscopy revealed a fibrotic stricture and multiple small orifices of pseudodiverticula with mild inflammatory changes. Biopsy specimens showed active chronic inflammatory changes of the mucosa with candidiasis. Dysphagia improved dramatically with esophageal dilation. However, the tiny diverticula did not resolve after treatment.

DOI： 10.1016/j.athoracsur.2006.01.062

1249 慎重な周術期管理を要した重症SLE合併進行食道癌の一例(食道癌治療2,一般演題,第61回日本消化器外科学会定期学術総会)

藤原康宏, 猶本良夫, 岩本高行, 金澤卓, 白川靖博, 山辻知樹, 藤原俊義, 岩垣博巳, 磯崎博司, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 1196 - 1196 2006.7

PD-8-3 消化器癌に対するテロメラーゼ活性を標的とした新規ウイルス療法の開発と臨床応用の可能性(消化器癌と分子生物学-臨床応用に向けて-,パネルディスカッション,第61回日本消化器外科学会定期学術総会)

藤原俊義, 香川俊輔, 宇野太, 寺石文則, 浦田泰生, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 975 - 975 2006.7

1225 胃原発性GISTの臨床病理学的および免疫組織学的検討 : hTERTの発現の検討を中心に(分子生物学2,一般演題,第61回日本消化器外科学会定期学術総会)

寺石文則, 宇野太, 香川俊輔, 藤原俊義, 合地明, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 1190 - 1190 2006.7

0005 放射線治療後に甲状腺低下を認めた食道癌患者の検討(食道良性1,一般演題,第61回日本消化器外科学会定期学術総会)

金澤卓, 猶本良夫, 湯浅壮司, 白川靖博, 山辻知樹, 藤原俊義, 松原長秀, 岩垣博巳, 松岡順治, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 1037 - 1037 2006.7

Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: Preclinical evaluation of chemovirotherapy

Toshiya Fujiwara, Shunsuke Kagawa, Hiroyuki Kishimoto, Yoshikatsu Endo, Masayoshi Hioki, Yoshihiro Ikeda, Ryo Sakai, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 119 ( 2 ) 432 - 440 2006.7

Language：English Publisher：WILEY-BLACKWELL

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.21846

当科におけるN4食道癌の治療

白川靖博, 猶本良夫, 岩本高行, 小林正彦, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 岩垣博巳, 松岡順治, 羽井佐実, 田中紀章

岡山医学会雑誌 118 ( 1 ) 85 - 85 2006.5

SLEを合併した進行食道癌の一切除例

岩本高行, 猶本良夫, 小林正彦, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 岩垣博巳, 松岡順治, 田中紀章

岡山医学会雑誌 118 ( 1 ) 85 - 85 2006.5

Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer

T Fujiwara, N Tanaka, S Kanazawa, S Ohtani, Y Saijo, T Nukiwa, K Yoshimura, T Sato, Y Eto, S Chada, H Nakamura, H Kato

JOURNAL OF CLINICAL ONCOLOGY 24 ( 11 ) 1689 - 1699 2006.4

Language：English Publisher：AMER SOC CLINICAL ONCOLOGY

Purpose
To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC).
Patients and Methods
Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 X 10(9) to 1 X 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m(2)). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response.
Results
Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the Carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease.
Conclusion
Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

DOI： 10.1200/JCO.2005.03.4116

追加発言 : テロメラーゼ特異的GFP蛍光発現ウイルス製剤OBP-401を用いた消化器癌微小転移のin vivoイメージング・システムの開発

児島亨, 藤原俊義, 岸本浩行, 橋本悠里, 香川俊輔, 宇野太, 浦田泰生, 田中紀章

日本外科学会雑誌 107 ( 2 ) 176 - 176 2006.3

K-ras変異型腫瘍に対するプロテアソームインヒビターbortezomibの有用性およびその作用機序に関する検討

寺石文則, Fang Bingliang, Liu Jinsong, 白澤専二, 笹月健彦, 香川俊輔, 藤原俊義, 田中紀章

日本外科学会雑誌 107 ( 2 ) 607 - 607 2006.3

Three cases of adenocarcinoma arising in extremely long-segment Barrett's esophagus

T Fujiwara, Y Naomoto, T Yamatsuji, Y Shirakawa, H Noguchi, T Fujiwara, N Oohara, M Gunduz, H Nagatsuka, M Nishie, H Uetsuka, S Hamazaki, N Tanaka

DIGESTIVE DISEASES AND SCIENCES 51 ( 3 ) 533 - 538 2006.3

Histone deacetylase inhibitor FR901228 enhances the antitumor effect of telomerase-specific replication-selective adenoviral agent OBP-301 in human lung cancer cells

T Watanabe, M Hioki, T Fujiwara, M Nishizaki, S Kagawa, M Taki, H Kishimoto, Y Endo, Y Urata, N Tanaka, T Fujiwara

EXPERIMENTAL CELL RESEARCH 312 ( 3 ) 256 - 265 2006.2

Language：English Publisher：ELSEVIER INC

Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus OBP-301 (Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of EIA and El B genes linked with an internal ribosome entry site, could replicate in and causes selective lysis, of human cancer cells. Infection efficiency in target cancer cells is the most important factor that predicts the antitumor effects of OBP-301. The ob objectives of this study are to examine the effects of the histone deacetylase inhibitor FR901228 on the level of coxsackie and adenovirus receptor (CAR) expression and OBP-301-mediated oncolysis in human non-small cell lung cancer cell lines. Flow cytometric analysis revealed up-regulated CAR expression in A549 and H460 cells following treatment with 1 ng/ml of FR901228. which was associated with increased infection efficiency as confirmed by replication-deficient beta-galactosidase-expressing adenovirus vector. In contrast. neither CAR expression nor infection efficiency was affected by FR901228 in H1299 cells. To visualize and quantify viral replication in the presence of FR901228, we used 01311-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region. Fluorescence microscopy and flow cytometry showed that FR901228 increased GFP expression in A549 and 11460 cells following OBP-401 infection in a dose-dependent manner, but this effect did not occur in H1299 cells. In addition. OBP-301 and FR901228 demonstrated a synergistic antitumor effect in A549 cells in vitro, as confirmed by isobologram analysis. Our data indicate that FR901228 preferentially increases adenovirus infectivity via up-regulation of CAR expression, leading to a profound oncolytic effect, which may have a significant impact on the outcome of adenovirus-based oncolytic virotherapy. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2005.10.026

胃癌術後縦隔リンパ節再発による気管狭窄にステント+放射線治療が奏効した1例

香川俊輔, 藤原俊義, 西崎正彦, 徳永尚之, 合地明, 田中紀章

癌と化学療法 2006

Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer.

Takahashi K, Kohno T, Ajima R, Sasaki H, Minna JD, Fujiwara T, Tanaka N, Yokota J

Int J Oncol 2006

テロメラーゼ特異的に増幅するGFP蛋白を用いたマウスの固形腫瘍の胸膜播種の可視化

梅岡達生, 川嶋健, 香川俊輔, 寺石文則, 滝正樹, 京哲, 永井勝幸, 浦田泰生, 田中紀章, 藤原俊義

岡山医学会雑誌 2006

症例報告多発肝転移を伴う進行性胃癌に対するイリノテカンと低用量シスプラチン化学療法に併用したゲノシタビンに対する顕著な反応

寺石文則, 宇野太, 香川俊輔, 合地明, 藤原俊義, 田中紀章

癌と化学療法 2006

CPT-11+Low-Dose 5-FU+CDDP療法が著効した多発肝転移を有する噴門部胃癌の1例

香川俊輔, 藤原俊義, 徳永尚之, 西崎正彦, 宇野太, 寺石文則, 合地明, 松岡順治, 田中紀章

癌と化学療法 2006

早期診断し得た食道癌術後静脈血栓塞栓症の2例

金澤卓, 渡辺信之, 猶本良夫, 小林正彦, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 岩垣博巳, 松岡順治, 田中紀章

岡山医学会雑誌 2006

大学発ベンチャーの研究開発-悪性腫瘍に対するウイルス製剤Telomelysinの臨床開発-

藤原俊義, 田中紀章, 浦田泰生

Biotherapy 20,3,310-317 2006

大学発ベンチャーの研究開発：悪性腫瘍に対するウイルス製剤Telomelysinの臨床開発.

藤原俊義, 田中紀章, 浦田泰生

Biotherapy 20: 310-317 2006

主要癌の遺伝子治療研究の現況-肺癌-

藤原俊義, 田中紀章

Biotherapy 20,3,270-279 2006

主要癌の遺伝子治療研究の現況：肺癌.

藤原俊義, 田中紀章

Biotherapy 20: 270-279 2006

ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma

F Teralshi, S Kagawa, T Watanabe, Y Tango, T Kawashima, T Umeoka, M Nisizaki, N Tanaka, T Fujiwara

FEBS LETTERS 579 ( 19 ) 4069 - 4075 2005.8

Language：English Publisher：ELSEVIER SCIENCE BV

The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Getitinib, 'Iressa') blocks the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. TNF-related death apoptosis inducing ligand (TRAIL) acts as an anticancer agent. We investigated the antitumor effects of ZD-1839 alone or in combination with TRAIL against human esophageal squamous cell cancer (ESCC) lines. Although all ESCC cells expressed EGF receptor at a protein level, the effect of ZD1839 on cell growth did not correlate with the level of EGFR expression and phosphorylation of EGF receptor protein in ESCC lines. ZD1839 caused a dose-dependent growth arrest at GO-G, phase associated with increased p27 expression. As TE8 cells are resistant to TRAIL, we tested whether ZD1839 combined with TRAIL induced apoptosis of TE8 cells via the inhibition of EGF receptor signaling by ZD1839. ZD1839 inhibited the phosphorylation of Akt, and enhanced TRAIL-induced apoptosis via activation of caspase-3 and caspase-9, and inactivation of Bcl-xL. Our results indicated that ZD1839 has anti-cancer properties against human esophageal cancer cells. ZD1839 also augmented the anti-cancer activity of TRAIL, even in TRAIL-resistant tumors. These results suggest that treatment with ZD1839 and TRAIL may have potential in the treatment of ESCC patients. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2005.06.031

Alport 症候に合併した食道び漫性平滑筋腫の1例(食道・胃・十二指腸18, 第60回日本消化器外科学会総会)

西江学, 猶本良夫, 山辻知樹, 白川靖博, 浅海信也, 藤原俊義, 松原長秀, 岩垣博巳, 磯崎博司, 田中紀章

日本消化器外科学会雑誌 38 ( 7 ) 1209 - 1209 2005.7

Transcriptional blockade induces p53-dependent apoptosis associated with translocation of p53 to mitochondria

Y Arima, M Nitta, S Kuninaka, DW Zhang, T Fujiwara, Y Taya, M Nakao, H Saya

JOURNAL OF BIOLOGICAL CHEMISTRY 280 ( 19 ) 19166 - 19176 2005.5

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

The tumor suppressor p53 functions as a transcriptional activator to induce cell cycle arrest and apoptosis in response to DNA damage. Although p53 was also shown to mediate apoptosis in a manner independent of its transactivation activity, the mechanism and conditions that trigger such cell death have remained largely unknown. We have now shown that inhibition of RNA polymerase II-mediated transcription by α-amanitin or RNA interference induced p53-dependent apoptosis. Inhibition of pol II-mediated transcription resulted in down-regulation of p21(Cip1), which was caused by both transcriptional suppression and protein degradation, despite eliciting p53 accumulation, allowing the cells to progress into S phase and then to undergo apoptosis. This cell death did not require the transcription of p53 target genes and was preceded by translocation of the accumulated p53 to mitochondria. Our data thus suggested that blockade of pol II-mediated transcription induced p53 accumulation in mitochondria and was the critical factor for eliciting p53-dependent but transcription-independent apoptosis.

DOI： 10.1074/jbc.M410691200

Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 ('Telomelysin-RGD)

M Taki, S Kagawa, M Nishizaki, H Mizuguchi, T Hayakawa, S Kyo, K Nagai, Y Urata, N Tanaka, T Fujiwara

ONCOGENE 24 ( 19 ) 3130 - 3140 2005.4

Language：English Publisher：NATURE PUBLISHING GROUP

Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus (OBP-301, 'Telomelysin'), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES, could replicate in cancer cells, and causes selective lysis of cancer cells. We further constructed OBP-405 ('Telomelysin-RGD') that contains an RGD motif in the HI loop of the fiber knob. We examined whether OBP-405 could be effective in overcoming the limitations of OBP-301, specifically their inefficient infection into cells lacking the primary receptor, the coxsackievirus and adenovirus receptor ( CAR). By flow cytometric analysis, H1299 ( lung) and SW620 ( colorectal) tumor cells showed high levels of CAR expression, whereas LN444 ( glioblastoma), LNZ308 ( glioblastoma), and H1299-R5 ( lung) tumor cells were negative for CAR expression. A quantitative realtime PCR analysis demonstrated that fiber-modified OBP-405 infected more efficiently than OBP-301, although the intracellular replication rate of both viruses was consistent. The comparative antitumor effect of fiber-modified OBP-405 and unmodified OBP-301 for human cancer cells was evaluated in vitro by XTT assay as well as in vivo by using athymic mice carrying xenografts. OBP-405 had a profound oncolytic effect on human cancer cell lines compared to OBP-301, in particular on cells with low CAR expression. Intratumoral injection of 107 plaque-forming units of OBP-405 into CAR-negative H1299-R5 lung tumor xenografts in nu/nu mice resulted in a significant inhibition of tumor growth and long-term survival in all treated mice. Moreover, selective replication of OBP-405 in the distant, uninjected H1299-R5 tumors was demonstrated. Our results suggest that fiber-modified replication-competent adenovirus OBP-405 exhibits a broad target range by increasing infection efficiency, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1038/sj.onc.1208460

肺悪性腫瘍のラジオ波治療

金澤右, 三村秀文, 郷原英夫, 向井敦, 平木隆夫, 長谷総一郎, 藤原寛康, 田尻展久, 佐野由文, 清水信義, 藤原俊義, 田中紀章

成人病と生活習慣病 2005

重症糖尿病合併胸部食道癌に対する糖質調整流動食Inslowの糖質・脂質代謝改善効果の検討

藤原俊哉, 猶本良夫, 元木崇之, 繁光薫, 白川靖博, 山辻知樹, 片岡正文, 羽井佐実, 羽井佐茂, 藤原俊義, 有馬裕史, 佐々木一, 松浦基, 田中紀章

外科治療 2005

Human monocyte-derived dendritic cells pulsed with wild-type p53 protein efficiently induce cytotoxic T-lymphocytes against p53-overexpressing human cancer cells.

Tokunaga N, Murakami T, Endo Y, Nishizaki M, Kagawa S, Tanaka N, Fujiwara T

Cancer Res 2005

癌に対する遺伝子治療：肺癌

藤原俊義, 香川俊輔, 田中紀章

遺伝子診療学（日本臨床増刊号） 63,507-511 2005

悪性腫瘍に対するウイルス製剤：Telomelysinの開発と臨床応用の可能性

藤原俊義, 田中紀章

Medical Technology 33,961-966 2005

P53遺伝子発現アデノウイルスベクターを用いた肺癌遺伝子治療

藤原俊義, 田中紀章

Surgery Frontier 12,53-56 2005

遊離空腸パッチグラフトによる頚部食道再建術

桜間一史, 猶本良夫, 野間和広, 浅海信也, 白川靖博, 山辻知樹, 藤原俊義, 松原長秀, 羽井佐実

岡山医学会雑誌 116 ( 3 ) 2005

Alport症候群に合併した食道びまん性平滑筋腫症の一例

西江学, 猶本良夫, 野間和広, 白川靖博, 浅海信也, 山辻知樹, 藤原俊義, 松原長秀, 羽井佐実, 岩垣博巳, 松岡順治, 田中紀章

岡山医学会雑誌 117 ( 2 ) 2005

食道癌術後にみられたToxic Shock Syndromeの検討

山辻知樹, 楢本良夫, 渡辺信之, 野間和広, 桜間一史, 小林正彦, 白川靖博, 小林直哉, 藤原俊義, 松原長秀, 羽井佐実, 岩垣博巳, 松岡順治, 田中紀章

日本臨床外科学会雑誌 66 2005

当科における食道部分切除術の検討

白川靖博, 猶本良夫, 野間和広, 西江学, 浅海信也, 山辻知樹, 藤原俊義, 松原長秀, 羽井佐実, 岩垣博巳, 松岡順治, 田中紀章

岡山医学会雑誌 117 ( 2 ) 2005

DP皮弁を用いた食道再建法

猶本良夫, 渡辺信之, 野間和広, 桜間一史, 小林正彦, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 岩垣博巳, 田中紀章

日本臨床外科学会雑誌 66 2005

集学的治療が奏功した胸部大動脈浸潤食道癌の一例

西江学, 猶本良夫, 野間和弘, 浅海信也, 白川靖博, 山辻知樹, 藤原俊義, 松原長秀, 岩垣博己, 田中紀章

岡山医学会雑誌 117 ( 2 ) 2005

Gene therapy for lung cancer

Toshiyoshi Fujiwara, Shunsuke Kagawa, Noriaki Tanaka

Nippon rinsho. Japanese journal of clinical medicine 63 507 - 511 2005

Free jejunal graft for hypopharyngeal and esophageal reconstruction

Y Shirakawa, Y Naomoto, K Noma, R Ono, T Nobuhisa, M Kobayashi, T Fujiwara, H Noguchi, T Ohkawa, T Yamatsuji, M Haisa, J Matsuoka, M Gunduz, N Tanaka

LANGENBECKS ARCHIVES OF SURGERY 389 ( 5 ) 387 - 390 2004.10

Language：English Publisher：SPRINGER

Aims: This study assessed the techniques of the free jejunal graft for the reconstruction of hypopharynx or cervical esophagus and discussed the main aspects related to those procedures. Methods and results: By using free jejunal grafts, we reconstructed 54 hypopharyngeal and cervical esophageal cancers. In this study, 23 out of 54 patients had a malignant tumor located in the hypopharynx and 31 in the cervical esophagus (27 primary cases and four secondary cases). Despite the multi-step and time-consuming procedure, we did not incur any trans-operative complication. Furthermore, we undertook the larynx preserving cervical esophagectomy and free jejunal graft reconstruction in six patients with cervical esophageal cancer, and those patients acquired a good quality of life. Conclusion: For the reconstruction of hypopharynx or cervical esophagus, the free jejunal graft is a very useful technique and improves the patient's quality of life.

DOI： 10.1007/s00423-004-0501-z

Visualization of intrathoracically disseminated solid tumors in mice with optical imaging by telomerase-specific amplification of a transferred green fluorescent protein gene

Tatsuo Umeoka, Takeshi Kawashima, Shunsuke Kagawa, Fuminori Teraishi, Masaki Taki, Masahiko Nishizaki, Satoru Kyo, Katsuyuki Nagai, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

Cancer Research 64 ( 17 ) 6259 - 6265 2004.9

Language：English

Currently available methods for detection of tumors in vivo such as X-ray, computed tomography, and ultrasonography are noninvasive and have been well studied
the images, however, are not specific for tumors. Direct optical imaging of tumor cells in vivo that can clearly distinguish them from surrounding normal tissues may be clinically useful. Here, we describe a new approach to visualizing tumors whose fluorescence can be detected using tumor-specific replication-competent adenovirus (OBP-301, Telomelysin) in combination with Ad-GFP, a replication-deficient adenovirus expressing green fluorescent protein (GFP). Human telomerase reverse transcriptase is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. We constructed an adenovirus 5 vector in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site and showed that OBP-301 replicated efficiently in human cancer cells, but not in normal cells such as human fibroblasts. When the human lung and colon cancer cell lines were infected with Ad-GFP at a low multiplicity of infection, GFP expression could not be detected under a fluorescence microscope
in the presence of OBP-301, however, Ad-GFP replicated in these tumor cells and showed strong green signals. In contrast, coinfection with OBP-301 and Ad-GFP did not show any signals in normal cells such as fibroblasts and vascular endothelial cells. We also found that established subcutaneous tumors could be visualized after intratumoral injection of OBP-301 and Ad-GFP. A549 human lung tumors and SW620 human colon tumors transplanted into BALB/c nu/nu mice were intratumorally injected with 8 × 105 plaque-forming units of Ad-GFP in combination with 8 × 106 plaque-forming units of OBP-301. Within 3 days of treatment, the fluorescence of the expressed GFP became visible by a three-chip color cooled charged-coupled device camera in these tumors, whereas intratumoral injection of Ad-GFP alone could not induce GFP fluorescence. Moreover, intrathoracic administration of Ad-GFP and OBP-301 could visualize disseminated A549 tumor nodules in mice after intrathoracic implantation. Our results indicate that intratumoral or intrathoracic injection of Ad-GFP in combination with OBP-301 might be a useful diagnostic method that provides a foundation for future clinical application.

DOI： 10.1158/0008-5472.CAN-04-1335

テロメラーゼ特異的制限増殖型アデノウイルスTelomelysinと微小管作用型抗癌剤の併用効果の検討

藤原俊哉, 藤原俊義, 香川俊輔, 滝正樹, 岸本浩行, 渡辺貴紀, 遠藤芳克, 京哲, 水口裕之

日本癌学会総会記事 63rd 510 2004.8

PPS-2-026 p53蛋白質をパルスしたヒト抹消血単核球由来の樹状細胞を用いた胃癌の新しい免疫療法(胃分子生物2)

香川俊輔, 藤原俊義, 徳永尚之, 西崎正彦, 松岡順治, 合地明, 田中紀章

日本消化器外科学会雑誌 37 ( 7 ) 1214 - 1214 2004.7

Antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene

Takayoshi Murakami, Naoyuki Tokunaga, Toshihiko Waku, Shinya Gomi, Shunsuke Kagawa, Noriaki Tanaka, Toshiyoshi Fujiwara

Clinical Cancer Research 10 ( 11 ) 3871 - 3880 2004.6

Language：English

Purpose: Dendritic cells (DCs) are attractive effectors for cancer immunotherapy because of their potential to function as professional antigen-presenting cells for initiating cellular immune responses. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and ∼50% of human malignancies exhibit mutation and aberrant expression of p53. We investigated the antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene. Experimental Design: We examined whether intratumoral administration of DCs infected with recombinant adenovirus expressing murine wild-type p53 (Ad-mp53) could induce systemic antitumor responses against mutant p53-expressing tumors, highly immunogenic MethA, or weakly immunogenic MCA-207 implanted in syngeneic mice. Results: Accumulation of wild-type p53 protein in bone marrow-derived murine DCs could he successfully achieved by Ad-mp53 infection. Treatment with intratumoral injection of Ad-mp53-transduced DCs caused a marked reduction in the in vivo growth of established MethA and MCA-207 tumors with massive cellular infiltrates. Administration of p53-expressing DCs suppressed the growth of both injected MCA-207 tumors and untreated distant MCA-207 tumors, but not unrelated Lewis lung carcinoma tumors, suggesting the augmentation of systemic immunogenicity against MCA-207 tumor cells. Moreover, intratumoral injection of p53-expressing DCs had a greater antitumor effect than did s.c. immunization. Conclusions: Our results indicate that intratumoral administration of DCs expressing murine wild-type p53 leads to significant systemic immune responses and potent antitumor effects in mutant p53-expressing murine cancer models. These findings raise the possibility of using this strategy of intratumoral injection of p53-expressing DCs for human cancer treatment.

DOI： 10.1158/1078-0432.CCR-03-0599

Thoracic tumors treated with CT-guided radiofrequency ablation: Initial experience

K Yasui, S Kanazawa, Y Sano, T Fujiwara, S Kagawa, H Mimura, S Dendo, T Mukai, H Fujiwara, T Iguchi, T Hyodo, N Shimizu, N Tanaka, Y Hiraki

RADIOLOGY 231 ( 3 ) 850 - 857 2004.6

Language：English Publisher：RADIOLOGICAL SOC NORTH AMERICA

PURPOSE: To determine the effectiveness of computed tomography (CT)-guided radiofrequency (RF) ablation of malignant thoracic tumors.
MATERIALS AND METHODS: CT-guided RF ablations of 99 malignant thoracic tumors (3-80 mm in largest diameter; mean, 19.5 mm) were performed in 35 patients in 54 sessions. Ablation was performed with an RF generator by using a single internally cooled electrode. Tumors were both primary (three lesions) and, secondary (pulmonary or pleural metastases, 96 lesions). Follow-up was 1-17 months (mean, 7.1 months). Follow-up CT and histopathologic examinations were evaluated. Univariate analysis was performed with the Fisher exact test and Welch, t test was used to evaluate differences between group means. P < .05 represented a significant difference. The maximal diameter of each residual tumor or local recurrence or the proportion of primary lesions of pulmonary metastatic tumors with recurrence after RF ablation were analyzed. Complications, management, and outcomes of the complications were recorded.
RESULTS: The appearance of each ablation zone, including the target tumor and surrounding normal lung parenchyma, showed involution at follow-up CT. Local recurrence was demonstrated histopathologically or radiologically in nine tumors. The other 90 tumors showed no growth progression at follow-up CT. Probable complete coagulation necrosis obtained with initial RF ablation was achieved in 91% (90 of 99) of the tumors. The mean maximal diameter of the nine tumors (19.6 mm +/- 7.7 [SD]) was not significantly different (P = .994) from that of the other 90 tumors (19.5 mm +/- 13.0). Primary lesions of those nine metastatic tumors varied and did not demonstrate a specific tendency. Complications included pneumothorax, fever higher than 37.5&DEG;C, hemoptysis, cough, pleural effusion, abscess formation, and hemothorax. The overall complication rate was 76% (41 of 54 sessions).
CONCLUSION: RF ablation seems to be a promising treatment for malignant (C) RSNA, 2004.

DOI： 10.1148/radiol.2313030347

Late resistance to adenoviral p53-mediated apoptosis caused by decreased expression of Coxsackie-adenovirus receptors in human lung cancer cells

Yasuhisa Tango, Masaki Taki, Yoshiko Shirakiya, Shoichiro Ohtani, Naoyuki Tokunaga, Yosuke Tsunemitsu, Shunsuke Kagawa, Toru Tani, Noriaki Tanaka, Toshiyoshi Fujiwara

Cancer Science 95 ( 5 ) 459 - 463 2004.5

Language：English

Adenovirus-mediated wild-type p53 gene transfer induces apoptosis in a variety of human cancer cells. Although clinical trials have demonstrated that a replication-deficient recombinant adenovirus expressing the wild-type p53 gene (Ad-p53) is effective in suppressing growth of non-small cell lung cancer (NSCLC), we often experienced late resistance to this treatment. To elucidate the mechanism of late resistance to Ad-p53 in human lung cancer cells, we generated 5 different resistant variants from p53-susceptible H1299 NSCLC cells by repeated infections with Ad-p53. We first examined the transduction efficiency of adenoviral vector by Ad-LacZ transduction followed by X-gal staining in parental and 5 resistant H1299 cell lines. Their sensitivity to viral infection decreased in correlation with the magnitude of resistance, and Ad-p53-mediated tumor suppression could be restored by dose escalation of Ad-p53 in the resistant variants. The expression of Coxsackie and adenovirus receptor (CAR) and αV integrins, which are cellular receptors for attachment and internalization of the virus, respectively, was next investigated in these cell lines. Flow cytometry revealed that αVβ3 and αVβ5 integrin expression was consistent, while p53-resistant cell lines showed that diminished CAR expression correlated with the magnitude of the resistance. Our results demonstrated that decreased CAR expression could be one of the mechanisms of late resistance to Ad-p53, which may have a significant impact on the outcome of adenovirus-based cancer gene therapy.

DOI： 10.1111/j.1349-7006.2004.tb03232.x

Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer

Y Tsunemitsu, S Kagawa, N Tokunaga, S Otani, T Umeoka, JA Roth, B Fang, N Tanaka, T Fujiwara

GUT 53 ( 4 ) 554 - 560 2004.4

Language：English Publisher：B M J PUBLISHING GROUP

Background: Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for various cancers. We recently developed a binary adenoviral vector system that can express the strong proapoptotic gene Bax (Ad/ PGK-GV16+ Ad/ GT-Bax: Ad/Bax).
Aims: To evaluate the potential of Bax gene therapy for gastric cancer, we assessed its antitumour effect in comparison with that of p53.
Methods: The human gastric cancer cell lines MKN-1, MKN-7, MKN-28, and MKN-45 were treated with Ad/ Bax or Ad/ p53, and cell viability, transgene expression, and caspase activation were assessed in vitro. To compare the antitumour effects of Ad/ Bax and Ad/ p53 treatment in vivo, subcutaneous tumours and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each mouse underwent intratumoral or intraperitoneal administration of viruses and the growth of implanted tumours was observed after treatment.
Results: Treatment with Ad/ Bax and Ad/ p53 resulted in marked Bax and p53 protein expression and effective apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN-45 cells showed resistance to Ad/ p53 and only treatment with Ad/ Bax resulted in activation of caspase 3 expression and massive apoptosis. Ad/ Bax treatment was more effective in suppressing both subcutaneous and peritoneally disseminated MKN-45 tumours compared with Ad/ p53 treatment.
Conclusion: Ad/ Bax treatment significantly inhibited the growth of even p53 resistant gastric cancer in vitro and in vivo. Therefore, adenovirus mediated Bax gene transfer may be useful in gene therapy for gastric cancers.

DOI： 10.1136/gut.2003.021683

制限増殖型ウイルス製剤を用いたMolecular Surgery:癌微小転移に対する治療戦略として

滝正樹, 藤原俊義, 水口裕之, 岸本浩行, 藤原俊哉, 香川俊輔, 西崎正彦, 京哲, 田中紀章

日本外科学会雑誌 105 278 2004.3

PS-156-3 非小細胞肺癌に対するp53を標的とした新たな遺伝子治療の前臨床試験 : 化学療法/ 放射線療法/ p53遺伝子治療の3者併用療法の基礎実験

西崎正彦, 藤原俊義, 香川俊輔, Roth Jack A., 田中紀章

日本外科学会雑誌 105 580 - 580 2004.3

Preoperative concurrent chemoradiotherapy with cisplatin and docetaxel in patients with locally advanced non-small-cell lung cancer

H Katayama, H Ueoka, K Kiura, M Tabata, T Kozuki, M Tanimoto, T Fujiwara, N Tanaka, H Date, M Aoe, N Shimizu, M Takemoto, Y Hiraki

BRITISH JOURNAL OF CANCER 90 ( 5 ) 979 - 984 2004.3

Language：English Publisher：NATURE PUBLISHING GROUP

The objective of this study was to assess the feasibility and effectiveness of an induction chemoradiotherapy regimen followed by surgery in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). A total of 22 patients with LA-NSCLC were treated with induction chemoradiotherapy consisting of cisplatin (40 mg m(-2)) and docetaxel (40 mg m(-2)) given on days 1, 8, 29 and 36 plus concurrent thoracic irradiation at a dose of 40-60 Gy (2 Gy fraction(-1) day(-1)). Surgical resection was performed within 6 weeks after completion of induction therapy. Objective response to the induction therapy was obtained in 16 patients (73%). In all, 20 patients (91%) underwent surgery and complete resection was achieved in 19 patients (86%). Pathological downstaging and pathological complete response were obtained in 14 (64%) and five (23%) patients, respectively. With a median follow-up period of 32 months, the calculated 3-year overall and progression-free survival rates were 66 and 61%, respectively. It is noteworthy that the 3-year overall survival rate in 14 patients achieving pathological downstaging was extremely high (93%). Toxicity was manageable with standard approaches. No treatment-related deaths occurred. This combined modality treatment is feasible and highly effective in patients with LA-NSCLC. The results warrant further large-scale study to confirm the effectiveness of this regimen.

DOI： 10.1038/sj.bjc.6601624

Telomerase-Specific Replication-Selective Virotherapy for Human Cancer

Takeshi Kawashima, Shunsuke Kagawa, Naoya Kobayashi, Yoshiko Shirakiya, Tatsuo Umeoka, Fuminori Teraishi, Masaki Taki, Satoru Kyo, Noriaki Tanaka, Toshiyoshi Fujiwara

Clinical Cancer Research 10 ( 1 I ) 285 - 292 2004.1

Language：English

Purpose: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells. Experimental Design: We constructed an adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (TRAD)], in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human cancer cells in vitro and in vivo. Results: TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying s.c. human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors, despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, noninjected tumors was demonstrated. Conclusions: Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1158/1078-0432.CCR-1075-3

Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo.

Ohtani S, Kagawa S, Tango Y, Umeoka T, Tokunaga N, Tsunemitsu Y, Roth JA, Taya Y, Tanaka N, Fujiwara T

3: 93-100, 2004 2004.1

Antitumoe Effect of Intratumoral Administratio of Bone Marrow-Derived Dendritic Cells Transduced with Wild-Type p53 Gene

Murakami T, Tokunaga N, Waku T, GOmi S, Kagawa S, Tanaka N, Fujiwara T

Clinical Cancer Research 2004

臨床：内科再度からみた肺癌診療の最近の話題 ADVEXINによる非詳細某肺癌の遺伝子治療

藤原俊義, 田中紀章

現代医療 2004

Long-Barrett食道に発生した表剤型食道腺癌の1例

水野憲治, 猶本良夫, 山辻知樹, 白川靖博, 大川尚臣, 信久徹治, 松本朝子, 上塚大一, 松原長秀, 藤原俊義, 岩垣博巳, 松岡順治, 田中紀章

消化器外科 2004

遺伝子治療の最前線テロメラーゼ活性を標的とした新規アデノウイルス製剤(Telomelysin:OBP-301)の開発

藤原俊義, 香川俊輔, 西崎正彦, 徳永尚之, 田中紀章, 永井勝幸, 浦田泰生, 岡山大遺伝子, 細胞治療センター, オンコリスバイオファーマ

日本癌治療学会誌 2004

肺癌遺伝子治療,最新の話題.

藤原俊義

Pulmonary Oncology Report 2004

進行非小細胞肺癌に対してp53遺伝子治療を施行し奏効が得られた一例

香川俊輔, 大谷彰一郎, 田中紀章, 藤原俊義

癌と化学療法 2004

Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition.

Arima, Y, Hirota, T, Bronner, C, Mousli, M, Fujiwara, T, Niwa, S, Ishikawa, H, Saya, H

Genes Cells 2004

Quantitative analusis of p53-targeted gene expression and visualization of p53 trascriptional activity following intratumoral administration of adenoviral p53 in vivo

Ohtani S, Kagawa S, Tango Y, Umeoka T, Tokunaga N, Tsunemitsu Y, Jack A. Roth, Taya Y, Tanaka N, Fujiwara T

Molecular Cancer Therapeutics 2004

Telomerase-Specific Repliccation-Selective Virotherapy for Human Cancer

Kawashima T, Kagawa S, Kobayashi N, Shirakiya Y, Umeoka T, Teraishi F, Taki M, Kyo S, Tanaka N, Fujiwara T

Clinical Cancer Research 2004

進行非小細胞肺癌に対してp53遺伝子治療を施行し奏効が得られた1例

香川俊輔, 藤原俊義, 大谷彰一郎, 田中紀章, 岡山大病院, 遺伝子, 細胞治療センタ

癌と化学療法 2004

化学療法 3 切除不能再発胃癌患者に対するIFP療法

松岡順治, 西崎正彦, 香川俊輔, 藤原俊義, 合地明, 猶本良夫, 田中紀章, 大, 消化器腫瘍外

日本癌治療学会誌 2004

遺伝子治療胃癌腹膜播種モデルにおけるBax遺伝子の抗腫瘍効果

香川俊輔, 藤原俊義, 常光洋輔, 徳永尚之, 大谷彰一郎, 梅岡達生, 西崎正彦, 田中紀章, 岡山大遺伝子, 細胞治療センタ

日本癌治療学会誌 2004

Late resistance to adenoviral p53-mediated apoptosis caused by decreased expression of Coxsackie-adenovirus receptors in human lung cancer cells

Tango Y, Taki M, Shirakiya Y, Ohtani S, Tokunaga N, Tsunemitsu Y, Kagawa S, Tani T, Tanaka N, Fujiwara T

Cancer Sci 2004

Visualization of Intrathoracically Disseminated Solid Tumors in Mice with Optical Imaging by Telomerase-Specific Amplification of a Transferred Green Fluorescent Protein Gene

Umeoka T, Kawashima T, Kagawa S, Teraishi F, Taki M, Nishizaki M, Kyo S, Nagai K, Urata Y, Tanaka N, Fujiwara T

Cancer Reaserch 2004

A novel method for gene delivery and expression in esophageal epithelium with fibrin glues containing replication-deficient adenovirus vector

F Teraishi, T Umeoka, T Saito, T Tsukagoshi, N Tanaka, T Fujiwara

SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES 17 ( 11 ) 1845 - 1848 2003.11

Language：English Publisher：SPRINGER-VERLAG

Background: Gene transfer to the esophageal epithelium holds the potential for the therapy of malignant as well as premalignant lesions in the upper gastrointestinal tract. Replication-deficient recombinant adenoviruses represent an efficient means of introducing genes in vivo into cells in a variety of organs. The majority of in vivo studies utilize direct submucosal injection for delivery of the viral vectors into the locoregional area of the gut; transferring genes into epithelial cells, however, is difficult because viruses are retained in the subepithelial space. To establish the efficient method for gene transfer into the epithelial cells, we have developed a multiluminal spray catheter that can be passed through the accessory channel of an endoscope, and we have evaluated the feasibility of fibrin glues as a vehicle of recombinant adenoviruses in a porcine model.
Methods: The fibrinogen solution and the thrombion solution containing an E1/E3 deleted recombinant adenovirus expressing the bacterial lacZ gene (Ad-lacZ) were endoscopically sprayed on the porcine esophagus through the catheter attached to the dual-barrel syringe. Twenty-four hours after gene delivery, beta-galactosidase activity of the esophagus was determined under the microscope following X-gal staining.
Results: The fibrin glue could be locally sprayed on the porcine esophagus by using the multichannel catheter through the endoscope. Attachment of the fibrin glue comtining Ad-lacZ caused strong beta-galactosidase staining on epithelial cells in the mucosal surface, but not in the basal cell layer.
Conclusion: Endoscopic local delivery of recombinant adenoviruses in aerosolized fibrin glues through a multiluminal catheter could provide an optimal technique for gene transfer into epithelial cells in the mucosal surfece, which may have important implications for the treatment of human esophageal premalignant diseases.

DOI： 10.1007/s00464-003-8146-5

RGDファイバー変異を挿入した腫よう特異的増殖可能アデノウイルス(TRAD)の抗腫よう効果の増強

滝正樹, 藤原俊義, 川嶋健, 岸本浩行, 藤原俊哉, 水口裕之, 京哲, 香川俊輔, 西崎正彦

日本癌学会総会記事 62nd 161 2003.8

蛍光イメージングによる癌特異的GFP遺伝子発現の検出: 癌特異的増殖可能アデノウイルスを用いた非侵襲的な生体内癌組織診断

梅岡達生, 藤原俊義, 川嶋健, 常光洋輔, 京哲, 香川俊輔, 西崎正彦, 田中紀章

日本外科学会雑誌 104 183 2003.4

制限増殖型アデノウイルスによる術前・術後補助療法の可能性: テロメラーゼ発現ヒト癌細胞における選択的腫よう融解による抗腫よう効果の検討

川嶋健, 藤原俊義, 滝正樹, 梅岡達生, 京哲, 西崎正彦, 香川俊輔, 田中紀章

日本外科学会雑誌 104 530 - 531 2003.4

癌に対する遺伝子治療の現況と展望 : 非増殖型ベクターから制限増殖型ベクターへ,さらに局所療法から全身療法へ

藤原俊義, 香川俊輔, 西崎正彦, 田中紀章

日本外科学会雑誌 104 191 - 192 2003.4

胃癌細胞に対するBaxアデノウイルスベクターの抗腫瘍効果 : 胃癌腹膜播種に対する補助療法としての可能性

常光洋輔, 香川俊輔, 渡辺貴紀, 藤原俊義, 田中紀章

日本外科学会雑誌 104 252 - 252 2003.4

ヒト末梢血単核球由来の樹状細胞とp53遺伝子あるいはp53蛋白質を用いた新しい免疫療法の開発

徳永尚之, 藤原俊義, 村上敬祥, 西崎正彦, 香川俊輔, 田中紀章

日本外科学会雑誌 104 527 - 527 2003.4

p53遺伝子治療におけるp53標的遺伝子発現の定量的解析とp53転写活性の可視化の試み : 術前アジュバント療法を目指して

大谷彰一郎, 藤原俊義, 梅岡達生, 丹後泰久, 香川俊輔, 西崎正彦, 田中紀章

日本外科学会雑誌 104 258 - 258 2003.4

Ectopic p21(sdi1) gene transfer induces retinoic acid receptor beta expression and sensitizes human cancer cells to retinoid treatment

F Teraishi, Y Kadowaki, Y Tango, T Kawashima, T Umeoka, S Kagawa, N Tanaka, T Fujiwara

INTERNATIONAL JOURNAL OF CANCER 103 ( 6 ) 833 - 839 2003.3

Language：English Publisher：WILEY-LISS

The biological effects of retinoic acid (RA) are mediated by nuclear retinoic acid receptors (RARs) that function as ligand-activated transcriptional factors. The response of human cancer cells to RA is known to be associated with the expression of RARbeta. Recent studies have demonstrated that the loss of RARbeta expression is involved in the development of a variety of human malignancies. We show that recombinant adenovirus-mediated p21(sdi1) gene transfer enhances RARbeta mRNA expression as well as protein expression and induces the sensitivity to all-trans RA (ATRA) in human cancer cells. Semi-quantitative reverse transcription-polymerase chain reaction analysis demonstrated that infection with adenovirus carrying human p21(sdi1) gene (AdSCMV-p21), which encodes a cyclin-dependent kinase inhibitor, induced RARbeta mRNA and protein expression in H1299 human non-small cell lung cancer cells and DLD-1 human colorectal cancer cells. We also found that exogenous introduction of the p21(sdil) gene transcriptionally activated the upstream promoter function of the RARbeta gene. Treatment with I muM of ATRA showed no significant inhibitory effects on the growth of H 1299 and DLD-1 cells; after Ad5CMV-p21 infection, however, cells underwent apoptosis with ATRA treatment at the same concentration, suggesting that p21(sdil) gene transfer sensitized H1299 and DLD-1 cells, presumably, through RARbeta upregulation. We also demonstrated the efficacy of intratumoral injection of AdSCMV-p21 in combination with systemic administration of ATRA in a nude mice xenograft model. Our results indicate that recombinant adenovirus-mediated p21(sdil) gene transfer could be potentially useful for the local induction of RA sensitivity in human premalignant and malignant lesions lacking appropriate RARbeta expression. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/ijc.10892

Protein transduction domains enable isolated islets to efficiently internalize the target protein

T Okitsu, N Kobayashi, T Totsugawa, M Maruyama, H Noguchi, T Watanabe, T Matsumura, T Fujiwara, N Tanaka

TRANSPLANTATION PROCEEDINGS 35 ( 1 ) 479 - 479 2003.2

Successful lentivirus-based delivery of a LacZ gene into human endothelial cells

T Totsugawa, N Kobayashi, M Maruyama, T Okitsu, H Noguchi, T Watanabe, T Matsumura, T Fujiwara, N Tanaka

TRANSPLANTATION PROCEEDINGS 35 ( 1 ) 499 - 500 2003.2

Lentiviral vector mediated gene delivery into non-dividing isolated islet cells

T Okitsu, N Kobayashi, T Totsugawa, M Maruyama, H Noguchi, T Watanabe, T Matsumura, T Fujiwara, N Tanaka

TRANSPLANTATION PROCEEDINGS 35 ( 1 ) 483 - 483 2003.2

Heparanase expression correlates with invasion and poor prognosis in gastric cancers.

Takaoka, M, Naomoto, Y, Ohkawa, T, Uetsuka, H, Shirakawa, Y, Uno, F, Fujiwara, T, Gunduz, M, Nagatsuka, H, Nakajima, M, Tanaka, N, Haisa, M

Lab. Invest. 2003

アデノウイルスを用いた遺伝子治療

藤原俊義, 田中紀章

Surgery Frontier 10,372-379 2003

制癌剤の新しい視点 1）アデノウイルスベクター

西崎正彦, 藤原俊義, 田中紀章

Surgery Frontier 10,201-207 2003

消化器癌におけるmolecular targeting療法としての遺伝子治療

藤原俊義, 田中紀章

G. I. Research 11,11-18 2003

肺癌の遺伝子治療

香川俊輔, 藤原俊義, 田中紀章

病理と臨床 21,519-522 2003

肺癌に対する遺伝子治療：その現況と展望

藤原俊義, 田中紀章

癌と化学療法 30,460-467 2003

遺伝子治療. 「肺癌：診断・治療の最前線」

藤原俊義, 田中紀章

癌の臨床（臨時増刊号） 49,1127-1136 2003

癌の遺伝子治療

藤原俊義, 田中紀章

医学のあゆみ「先端外科医療の最前線」 205,575-580 2003

遺伝子治療の実際

香川俊輔, 藤原俊義, 田中紀章

癌と化学療法 30,193-197 2003

複製可能ウイルスを用いた遺伝子治療の進歩：制限増殖型アデノウイルス

藤原俊義, 田中紀章

分子細胞治療 2,249-255 2003

肺癌治療と遺伝子多型

藤原俊義, 田中紀章

癌治療と宿主 15,29-34 2003

p53を標的とした治療

藤原俊義, 田中紀章

呼吸器科 4,401-409 2003

p53をターゲットとした肺癌治療

藤原俊義, 田中紀章

肺癌の臨床 5,295-302 2003

アポトーシス誘導遺伝子p53による癌の遺伝子治療

藤原俊義, 田中紀章

細胞 35,558-560 2003

Clinical study of adenoviral mediated p53 gene therapy for non-small cell lung cancer in Japan

Shunsuke Kagawa, Toshiyoshi Fujiwara, Noriaki Tanaka

Gan to kagaku ryoho. Cancer & chemotherapy 30 ( 2 ) 193 - 197 2003

Language：Japanese Publishing type：Book review, literature introduction, etc.

The prognosis in case of non-small cell lung cancer (NSCLC) remains poor, and novel treatment modalities are urgently needed for advanced NSCLC. Backed by advances in the understanding of cancer biology, gene therapy has been developed in recent years. The p53 gene is altered in over 50% of cancers and has been extensively studied as a tumor suppressor gene. Adenoviral-mediated p53 gene transfer is currently under clinical evaluation worldwide for the treatment of cancer. We are now conducting a phase I study of Ad-p53 for advanced NSCLC patients in Japan. As an interim report, we provide a brief summary of the current status of this study, highlighting the safety and clinical efficacy of Ad-p53. As of September 2002, 13 patients were enrolled to this study, and safety and antitumor effects have been noted.

肺癌に対する遺伝子治療の現状と展望 : 非増殖型ベクターから制限増殖型ベクターへ(肺癌における遺伝子情報とその応用)(ワークショップ8)

藤原俊義, 川嶋健, 香川俊輔, 西崎正彦, 田中紀章

肺癌 42 ( 5 ) 360 - 360 2002.10

非小細胞肺癌に対する集学的治療としてのp53遺伝子治療 : ドセタキセル/放射線療法との併用効果の基礎的検討

西崎正彦, 藤原俊義, 香川俊輔, 田中紀章, Ji Lin, Roth Jack

肺癌 42 ( 5 ) 403 - 403 2002.10

腫よう特異的増殖可能アデノウイルス(TRAD)の開発テロメラーゼ発現ヒト癌細胞における選択的腫よう融解の誘導

川嶋健, 藤原俊義, 梅岡達生, 滝正樹, 京哲, 香川俊輔, 西崎正彦, 田中紀章

日本癌学会総会記事 61st 186 2002.8

蛍光イメージングによる癌特異的GFP遺伝子発現の検出癌特異的増殖可能アデノウイルスを用いた非侵襲的な生体内癌組織診断

梅岡達生, 藤原俊義, 川嶋健, 常光洋輔, 京哲, 香川俊輔, 西崎正彦, 田中紀章

日本癌学会総会記事 61st 404 2002.8

Adenovirus-mediated p14ARF gene transfer cooperates with Ad5CMV-p53 to induce apoptosis in human cancer cells

Yasuhisa Tango, Toshiyoshi Fujiwara, Takahiro Itoshima, Yoshiko Takata, Kou Katsuda, Futoshi Uno, Shoichiro Ohtani, Tohru Tani, Jack A. Roth, Noriaki Tanaka

Human Gene Therapy 13 ( 11 ) 1373 - 1382 2002.7

Language：English

p14ARF, a product of theINK4A/ARF locus, induces p53 upregulation by neutralizing the effects of MDM2, a transcriptional target of p53 that antagonizes its function. Here we report that adenovirus-mediated p14ARF gene transfer leads to the accumulation of ectopically transduced p53 and to apoptosis in human cancer cells. We constructed an adenoviral vector expressing p14ARF (Ad-ARF) and examined its synergistic effect with p53-expressing adenovirus (Ad5CMV-p53 or Ad-p53) in human lung and esophageal cancer cells. Simultaneous Ad-ARF and Ad-p53 infection increased p53 protein levels not only in a wild-type p53-expressing cell line, but also in cell lines with deleted p53. This resulted in a significant in vitro cytotoxicity compared with Ad-p53 infection alone. Coinfection of Ad-ARF and Ad-p53 also resulted in an increase in expression of p53-inducible genes, including p21WAF-1/Cip1, p53R2, and Noxa. In addition, the growth of human lung cancer tumors subcutaneously implanted into nu/nu mice was inhibited significantly by intratumoral injection with Ad-ARF and Ad-p53. Our data demonstrate that overexpression of ectopic p14ARF may render cells more sensitive to p53-mediated apoptosis, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1089/104303402760128595

肺癌治療において遺伝子治療の目指すもの

藤原俊義, 宇野太, 香川俊輔, 片岡正文, 田中紀章

日本外科学会雑誌 103 81 - 81 2002.3

TRAIL遺伝子導入による癌細胞特異的apoptosis誘導とbystander効果

香川俊輔, 藤原俊義, 常光洋輔, 片岡正文, Fang Bingliang, 田中紀章

日本外科学会雑誌 103 127 - 127 2002.3

アデノウイルスベクターを用いたp14ARFおよびp53遺伝子導入による相乗的な抗腫瘍活性 : 作用機構とその臨床的有用性

丹後泰久, 藤原俊義, 糸島崇博, 片岡正文, 香川俊輔, 谷徹, 田中紀章

日本外科学会雑誌 103 237 - 237 2002.3

効果的なヒト細胞への遺伝子導入を目的としたレンチウイルスベクターシステムの開発

都津川敏範, 小林直哉, 興津輝, 野口洋文, 松村年久, 渡辺剛正, 丸山昌伸, 藤原俊義, 田中紀章

日本外科学会雑誌 103 527 - 527 2002.3

Activation of caspase-3 and cleavage of Rb are associated with p16-mediated apoptosis in human non-small cell lung cancer cells

K Katsuda, M Kataoka, F Uno, T Murakami, T Kondo, JA Roth, N Tanaka, T Fujiwara

ONCOGENE 21 ( 13 ) 2108 - 2113 2002.3

Language：English Publisher：NATURE PUBLISHING GROUP

The p16 tumor suppressor gene is frequently inactivated in human cancer tissues and cell lines. We previously reported that wild-type p16 expression from an adenovirus vector (Adv/p16) induced p53-dependent apoptotic cell death in non-small cell lung cancer (NSCLC) cell fines. Here we show the potential mechanism of apoptosis induced by Adv/p16 infection. Infection of human NSCLC cell line A549, which carries the wild-type p53 gene, with Adv/p16 resulted in activation of caspase-3, accompanied by the cleavage of its substrate poly (ADP-ribose) polymerase (PARP), on day 3 of infection. The retinoblastoma (Rb) cell cycle regulator protein was also cleaved after activation of caspase-3; when the levels of Rb significantly diminished, apoptosis began. When A549 cells were pretreated with the caspase-inhibitory peptide N-acetyl-asp-Glu-Val-Asp-CHO (aldehyde) (Ac-DEVD-CHO), Adv/p16-mediated apoptosis and Rb cleavage were greatly inhibited. Furthermore, MDM2, a negative regulator of p53 expression was upregulated 3 days after Adv/p16 infection, and MDM2 was subsequently cleaved by caspase-3; MDM2 cleavage was inhibited by Ac-DEVD-CHO treatment. These data implied that cleavage of Rb, in addition to activation of caspase-3, represented a mechanism by which Adv/p16 induced apoptotic cell death in human NSCLC cells. Our results support the clinical relevance of Adv/p16 as a treatment for p16-null human NSCLC that express wild-type p53.

DOI： 10.1038/sj/onc/1205272

p53 inhibits adriamycin-induced down-regulation of cyclin D1 expression in human cancer cells

JH Shao, F Teraishi, K Katsuda, N Tanaka, T Fujiwara

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 290 ( 3 ) 1101 - 1107 2002.1

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

The tumor suppressor p53 gene product is an essential component of the cytotoxic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We previously demonstrated that adenovirus-mediated wild-type p53 gene transfer could enhance the cytotoxic actions of chemotherapeutic drugs both in vitro and in vivo; however, the molecular mechanism of this chemosensitization is still unclear. Cyclin D1 is a major regulator of the progression of cells into the proliferative stage of the cell cycle. Here we show that infection with an adenovirus vector expressing the wild-type p53 gene (Ad-p53) caused an increase in cyclin D1 protein levels in human colorectal cancer cell lines DLD-1 and SW620; treatment with the anti-cancer drug adriamycin, however, down-regulated their cyclin D1 protein expression in a dose-dependent manner. The suppression of cyclin D1 expression following adriamycin treatment could be blocked by simultaneous Ad-p53 infection. Furthermore, DLD-1 and SW620 cells transfected with the cyclin D1 expression construct displayed increased sensitivity to adriamycin compared to that of the vector-transfected control. Our results suggest that ectopic wild-type p53 gene transfer results in increased cyclin D1 expression and, consequently, sensitizes human colorectal cancer cells to chemotherapeutic agents. (C) 2002 Elsevier Science (USA).

DOI： 10.1006/bbrc.2001.6314

Transduction of immortalized human hepatocytes with p21 to enhance differentiated phenotypes.

Kunieda T, Kobayashi N, Sakaguchi M, Okitsu T, Totsugawa T, Watanabe T, Matsumura T, Maruyama M, Noguchi H, Takesue M, Shibata N, Ohmoto K, Fujiwara T

Cell Transplant 2002

Lentiviral transfer of the LacZ gene into human endothelial cells and human bone marrow mesenchymal stem cells.

Totsugawa T, Kobayashi N, Okitsu T, Noguchi H, Watanabe T, Matsumura T, Maruyama M, Fujiwara T, Sakaguchi M, Tanaka N

Cell Transplantation 2002

Controlled expansion of human endothelial cell populations by Cre-loxP- based reversible immortalization.

Noguchi H, Kobayashi N, Westerman K A, Sakaguchi M, Okitsu T, Totsugawa T, Watanabe T, Matsumura T, Fujiwara T, Ueda T, Miyazaki M, Tanaka N, Leboulch P

Human Gene Therapy 2002

Adenovirus-Mediated p14ARF gene transfer cooperates with Ad5CMV-p53 to induce apoptosis in human cancer cells.

Tango Y, Fujiwara T, Itoshima T, Takata Y, Katsuda K, Uno F, Ohtani S, Tani T, Roth JA, Tanaka N

Human Gene Therapy 2002

Improvement in the differentiated hepatic phenotype of immortalized human hepatocytes by adenovirus mediated p21 gene transfer.

Kobayashi N, Sakaguchi M, Okitsu T, Totsugawa T, Maruyama M, Matsumura T, Watanabe T, Noguchi H, Kosaka Y, Fujiwara T, Tanaka N

Asaio J 2002

Gene therapy for cancer

FUJIWARA Toshiyoshi, TANAKA Noriaki

Nippon Nōgeikagaku Kaishi 76,4,385-387 ( 4 ) 385 - 387 2002

肺癌非手術療法の新しい試み 7.遺伝子治療.

片岡正文, 藤原俊義, 香川俊輔, 田中紀章

日本外科学会雑誌 103,2,244-249 2002

肺癌の遺伝子治療の現状と問題点.

藤原俊義, 田中紀章

臨床と研究 79,5,787-792 2002

肺癌に対する遺伝子治療：p53発現アデノウイルスベクターによる肺癌遺伝子治療臨床試験の現況.

香川俊輔, 藤原俊義, 田中紀章

医学のあゆみ 203,5,302-306 2002

p53遺伝子を用いた癌の遺伝子治療.

藤原俊義, 田中紀章

癌の臨床 48,6,303-311 2002

p53を用いた肺癌遺伝子治療.

香川俊輔, 藤原俊義, 田中紀章

日本臨床 60,Suppl 5, 630-634 2002

肺癌：局所療法としての遺伝子治療.

藤原俊義, 田中紀章

BIO Clinica 17,7,589-592 2002

レンチウイルスベクターシステム樹立に伴う安全配慮.

都津川敏範, 小林直哉, 丸山昌伸, 小坂芳和, 興津輝, 荒田尚, 阪口政清, 藤原俊義, 倉林譲, 田中紀章

Organ Biology 9,4,357-364 2002

p53遺伝子治療における抗腫瘍活性増強のストラテジー.

藤原俊義, 田中紀章

遺伝子医学 6,1,15-20 2002

特集今日の肺癌診療肺癌遺伝子治療の現状.

藤原俊義, 田中紀章

日本医師会雑誌 128,3,378 2002

Combination of tumor necrosis factor alpha and interferon alpha induces apoptotic cell death through a c-myc-dependent pathway in p53 mutant H226br non-small-cell lung cancer cell line

Y Yasuoka, Y Naomoto, T Yamatsuji, M Takaoka, M Kimura, H Uetsuka, N Matsubara, T Fujiwara, M Gunduz, N Tanaka, M Haisa

EXPERIMENTAL CELL RESEARCH 271 ( 2 ) 214 - 222 2001.12

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

We investigated the role of wild-type p53 and c-myc activity in apoptosis induced by a combination of natural human tumor necrosis factor alpha (TNF-alpha) and natural human interferon alpha (IFN-alpha). Studies were performed with two human non-small-cell lung cancer cell lines, H226b, which has wild-type p53, and H226br, which has a mutant p53. The combination of IFN-alpha and TNF-alpha significantly inhibited cell growth and induced apoptotic cell death of both H226b and H226br, compared with IFN-alpha or TNF-alpha alone. Treatment with one or both cytokines did not affect the expression level of p53 in both cell lines. These results suggest that the combination of IFN-alpha /TNF-alpha induces apoptotic cell death through a p53- independent pathway. The c-myc oncogene is known to be involved in apoptosis induced by TNF. Antisense c-myc oligonucleotides have been reported to modulate cell growth or apoptosis in several cell lines. Antisense oligodeoxynucleotides were added to the culture of H226br cells before the addition of IFN-alpha /TNF-alpha. Antisense c-myc inhibited IFN-alpha /TNF-alpha cytotoxicity and apoptotic cell death. In conclusion, this study provides support for the speculation that TNF-alpha /TFN-alpha induce apoptosis through a c-myc-dependent pathway rather than a p53-dependent pathway. (C) 2001 Elsevier Science.

DOI： 10.1006/excr.2001.5383

Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells

Takuya Fukazawa, Toshiyoshi Fujiwara, Futoshi Uno, Fuminori Teraishi, Yoshihiko Kadowaki, Takahiro Itoshima, Yoshiko Takata, Shunsuke Kagawa, Jack A. Roth, Jürg Tschopp, Noriaki Tanaka

Oncogene 20 ( 37 ) 5225 - 5231 2001.8

Language：English

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DRS-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transler.

DOI： 10.1038/sj.onc.1204673

S08-03 Cre/loxP部位特異的組換え反応を用いた可逆性不死化ヒト肝臓細胞の再生医療への応用

小林直哉, 野口洋文, 松村年久, 渡辺剛正, 都津川敏範, 藤原俊義, 田中紀章

日本消化器外科学会雑誌 34 ( 7 ) 832 - 832 2001.7

PD3-6 p53遺伝子異常を標的とした遺伝子治療:臨床試験の現況と問題点

藤原俊義, 片岡正文, 香川俊輔, 田中紀章

日本外科学会雑誌 102 51 - 51 2001.3

SF1f-4 SV40TagとhTERTによる不死化ヒト肝類洞内皮細胞株の樹立

松村年久, 小林直哉, 野口洋文, 渡邉剛正, 都津川敏範, 藤原俊義, 田中紀章

日本外科学会雑誌 102 67 - 67 2001.3

SF7c-2 肝細胞移植の発展に向けたテロメラーゼ遺伝子によるヒト肝細胞株の樹立

都津川敏範, 小林直哉, 野口洋文, 松村年久, 渡邉剛正, 藤原俊義, 田中紀章

日本外科学会雑誌 102 95 - 95 2001.3

SF13a-2 高性能バイオ人工肝の実現に向けたヒト肝細胞株の樹立と至適培養担体の開発

小林直哉, 野口洋文, 松村年久, 渡邉剛正, 都津川敏範, 藤原俊義, 田中紀章

日本外科学会雑誌 102 109 - 109 2001.3

SF13a-4 ヒト肝星様細胞へのレトロウイルスベクターによるテロメラーゼ遺伝子(hTERT)導入

渡辺剛正, 小林直哉, 野口洋文, 松村年久, 都津川敏範, 藤原俊義, 田中紀章

日本外科学会雑誌 102 110 - 110 2001.3

p53を用いた遺伝子治療

藤原俊義, 田中紀章

「癌治療の先端に迫る！」（実験医学増刊）（黒木登志夫、編集）pp2564-2571、羊土社、東京、2001. 2001.1

Insertion of suicide gene into an immortalized human hepatocyte cell line.

Kobayashi N, Noguchi H, Totsugawa T, Watanabe T, Matsumura T, Fujiwara T, Miyazaki M, Fukaya K, Namba M, Tanaka N

Cell Transplant 2001

Accelerated degradation of cellular FLIP prostein through the ubiquitinproteasome pathway in p53-mediated apoptosis of human cancer cells.

Fukazawa T, Fujiwara T, Uno F, Teraishi F, Kadowaki Y, Itoshima T, Takata Y, Kagawa S, Roth JA, Tschpp J, Tanaka N

Oncogene 2001

A tightly regulated immortalized human fetal hepatocyte cell line to develop a bioartificial liver.

Kobayashi N, Noguchi H, Watanabe T, Matsumura T, Totsugawa T, Fujiwara T, Tanaka N

Transplantation Proceedings 2001

Role of immortalized hepatocyte transplantation in acute liver failure.

Kobayashi N, Noguchi H, Watanabe T, Matsumura T, Totsugawa T, Fujiwara T, Tanaka N

Transplantation Proceedings 2001

Donor dendritic cells and recipient kupffer cells in the induction of donor-specific immune hyporesponsiveness.

Nakagawa K, Matsuno T, Iwagaki H, Morimoto Y, Fujiwara T, Sadamori H, Inagaki M, Urushihara N, Yagi T, Tanaka N

The Journal of International Medical Research 2001

A family of multiple endocrine Neoplasia Type 2A with the RET proto-oncogene mutation in codon 618 (Cys→Arg).

Nakao A, Naomoto Y, Kataoka M, Haisa M, Kataoka K, Saitoh S, Fujiwara T, Yamatsuji T, Shigemitsu K, Umeoka T, Isozaki H, Futami H, Yamaguchi K, Tanaka N

Japanese Journal of Clinical Oncology 2001

Rapidly functional immobilization of immortalized human hepatocytes using cell adhesive GRGDS peptide-carrying cellulose microspheres.

Kobayashi N, Taguchi T, Noguchi H, Okitsu T, Totsugawa T, Watanabe T, Matsumura T, Fujiwara T, Urata H, Kishimoto N, Hayashi N, Nakaji S, Murakami T, Tanaka N

Cell Transplantation 2001

Analysis of the immune status in the recipients with long-term well-functioning kidneys allograft.

Nakagawa K, Matsuno T, Iwagaki H, Fujiwara T, Tanaka N

Acta Medica Okayama 2001

Antisense-mediated suppression of human heparanase gene expression inhibits pleural dissemination of human cancer cells.

Uno F, Fujiwara T, Takata Y, Ohtani S, Katsuda K, Takaoka M, Ohkawa T, Naomoto Y, Nakajima M, Tanaka N

Cancer Research 2001

Expansion of human hepatocyte populations by a retroviral gene transfer of simian virus 40 large T antigen.

Kobayashi N, Westerman KA, Taguchi T, Sakaguchi M, Fujiwara T, Urata H, Kishimoto N, Hayashi N, Nakaji S, Murakami T, Leboulch P, Tanaka N

ASAIO Journal 2001

肺犬糸状虫症の１例.

児島亨, 片岡和彦, 片岡正文, 渋谷祐一, 安治俊樹, 藤原俊義, 田中紀章

胸部外科 2001

Asssessment of aortic invasion by pulmonary carcinoma with the use of intra-aortic endovascular sonography: A case report.

Yasui K, Kanazawa S, Mimura H, Fujiwara T, Kataoka M, Tanaka N, Hiraki Y

The Journal of Thoratic and Cardiovascular Surgery 2001

レンチウイルスベクターによるヒト血管内皮細胞への効果的な遺伝子導入.

都津川敏範, 小林直哉, 丸山昌伸, 興津輝, 野口洋文, 松村年久, 渡辺剛正, 阪口政清, 藤原俊義, 田中紀章

Organ Biology 2001

Alltrans-retinoic acid enhances the effect of adenovirus-mediated wild-type p53 gene transfer in head and neck squamous cell carcinoma.

Nakashima T, Sun SY, Lotan R, Fujiwara T, Yasumatsu R, Komiyama S, Clayman GL

Laryngoscope 2001

Successful retroviral gene transfer of simian virus 40 T antigen and herpes simplex virus-thymidne kinase into human hepatocytes.

Kobayashi N, Noguchi H, Westerman KA, Watanabe T, Matsumura T, Totsugawa T, Fujiwara T, Leboulch P, Tanaka N

Cell Transplant 2001

Construction of a differentiated human hepatocyte cell line expressing the herpes simplex virus-thymidne kinase gene.

Kobayashi N, Miyazaki M, Westerman KA, Noguchi H, Sakaguchi M, Totsugawa T, Watanabe T, Matsumura T, Fujiwara T, Leoboulch P, Tanaka N, Namba M

ASAIO Journal 2001

Cre/loxP-based reversible immortalization of human hepatocytes.

Kobayashi N, Noguchi H, Westerman KA, Watanabe T, Matsumura T, Totsugawa T, Fujiwara T, Leboulch P, Tanaka N

Cell Transplantation 2001

p53遺伝子を用いた癌の遺伝子治療.

藤原俊義, 田中紀章

臨床婦人科 55 ,8,922-927 2001

局所療法としての遺伝子治療?p53遺伝子製剤の安全性と臨床効果?.

藤原俊義, 片岡正文, 田中紀章

最新医学 56 ,増刊号, 262-273 2001

肺癌の遺伝子治療.

片岡正文, 藤原俊義, 田中紀章

呼吸 20 ,3,222-229 2001

特集肺癌の診断治療法における最近の進歩 4.化学療法の進歩肺癌の遺伝子治療.

片岡正文, 香川俊輔, 藤原俊義, 田中紀章

肺癌の臨床 4,2,221-230 2001

p53を発現するアデノウイルスベクターを用いたがん治療.

藤原俊義, 田中紀章

細胞 33,213-217 2001

Gene therapy approaches for the management of non-small cell lung cancer.

Roth JA, Grammer SF, Swisher SG, Komaki R, Nemunaitis J, Merritt J, Fujiwara T, Meyn RE Jr

Seminor of Oncology 28,50-56 2001

p53遺伝子を用いた肺癌の遺伝子治療.

香川俊輔, 藤原俊義, 片岡正文, 田中紀章

Lung Cancer Today 1 ,12-16 2001

p53遺伝子を用いた癌の遺伝子治療?Tumor dormancy therapyとしての可能性.

藤原俊義, 田中紀章

医学のあゆみ 198 ,6,7,451-455 2001

アデノウイルスベクターを用いた肺癌のp53遺伝子治療.

藤原俊義, 田中紀章

治療学 35 ,7,65-69 2001

p53を用いた肺癌の遺伝子治療-遺伝子製剤としての可能性-.

藤原俊義, 片岡正文, 田中紀章

肺癌の臨床 3,321-328 2001

p53を用いたがんの遺伝子治療-肺癌治療への応用-.

藤原俊義, 田中紀章

分子がん治療 2, 84-91 2001

p53遺伝子を用いた癌の遺伝子治療.

藤原俊義, 田中紀章

放射線生物研究 36,4,331-344 2001

呼吸器疾患に対する遺伝子治療.

香川俊輔, 藤原俊義, 片岡正文, 田中紀章

外科 63, 1740-1747 2001

ヒト不死化肝細胞株の樹立 Cre/loxPを用いたヒト肝細胞の増殖法.

小林直哉, 野口洋文, 都津川敏範, 松村年久, 渡辺剛正, 丸山昌伸, 松本朝子, 藤原俊義, 林伸幸, 中路修平, 田中紀章

外科 63 ,5,550-556 2001

アデノウイルスベクターを用いた肺癌の遺伝子治療.

藤原俊義, 田中紀章

医学のあゆみ 199,9,673-677 2001

遺伝子が変える21世紀の医療現場：p53遺伝子を用いた癌の遺伝子治療：肺癌への臨床応用.

藤原俊義, 片岡正文, 田中紀章

治療 83,161-166 2001

悪性腫瘍に対するがん抑制遺伝子治療研究の現状.

藤原俊義, 田中紀章

分子細胞治療 2 ,3,247-254 2001

肺癌の遺伝子治療.

藤原俊義, 田中紀章

Practical Oncology 14:,2-4 2001

肺癌の遺伝子治療.

藤原俊義, 田中紀章

外科治療 85,4,463-464 2001

6.肺癌のp53遺伝子導入による分子療法の現況と展望 : 癌の発生と転移の分子機構(第57回卒後教育セミナー講演要旨)

藤原俊義

日本外科学会雑誌 101 ( 9 ) 695 - 695 2000.9

PP1627 消化器癌におけるheparanaseの発現の意義の検討

高岡宗徳, 猶本良夫, 羽井佐実, 山辻知樹, 木村真士, 伴秀利, 繁光薫, 松原長秀, 藤原俊義, 田中紀章

日本消化器外科学会雑誌 33 ( 7 ) 1287 - 1287 2000.7

SF20-1 E2F-1遺伝子およびp53遺伝子発現アデノウイルスベクターの併用による効率的な食道癌の遺伝子治療

糸島崇博, 藤原俊義, 片岡正文, 門脇嘉彦, 深澤拓也, 邵江華, 和久利彦, 田中紀章, 小玉正智

日本外科学会雑誌 101 155 - 155 2000.3

PP-1384 全ての血族者に遺伝子診断を行った多発性内分泌腫瘍症(MEN)2Aの1家系

小坂芳和, 中尾篤典, 猶本良夫, 片岡正文, 羽井佐実, 片岡正文, 藤原俊義, 山辻知樹, 田中紀章

日本外科学会雑誌 101 553 - 553 2000.3

SF10-3 不死化ヒト臍帯静脈内皮細胞株(HNKT-1)の樹立

野口洋文, 小林直哉, 宮崎正博, 井上祐介, 阪口政清, 藤原俊義, 田中紀章

日本外科学会雑誌 101 129 - 129 2000.3

PP-686 vIL-10導入ラット肝細胞スフェロイドの同種脾内移植

岡田豊, 斎藤信也, 藤澤憲司, 八木孝仁, 藤原俊義, 中尾篤典, 松川啓義, 貞森裕, 稲垣優, 松野剛, 田中紀章

日本外科学会雑誌 101 379 - 379 2000.3

SP2-1 癌に対する遺伝子治療の現状と展望 : p53遺伝子治療から新しい分化誘導療法まで

藤原俊義, 門脇嘉彦, 香川俊輔, 片岡正文, 田中紀章

日本外科学会雑誌 101 54 - 54 2000.3

A PHASE I TRIAL OF ADENOVIRAL p53 GENE THERAPY FOR NON-SMALL CELL LUNG CANCER

FUJIWARA Toshiyoshi, KATAOKA Masafumi, KAWAMATA Osamu, TANAKA Noriaki

Journal of Japan Surgical Society 100 ( 11 ) 749 - 755 1999.11

p53遺伝子導入によるアポトーシス誘導:癌遺伝子治療への応用

藤原俊義, 深澤拓也, 田中紀章

Biotherapy today 6 ( 1 ) 16 - 22 1999.6

O-91 遺伝子導入肝細胞の同種、異種移植

岡田豊, 斉藤信也, 中尾篤典, 松川啓義, 藤澤憲司, 遠藤彰, 松田浩明, 大石正博, 藤原俊義, 八木孝仁, 田中紀章

日本外科学会雑誌 100 130 - 130 1999.2

O-314 p53遺伝子導入による腫瘍血管新生の抑制

西崎正彦, 藤原俊義, 片岡正文, 中村祐輔, 田中紀章

日本外科学会雑誌 100 186 - 186 1999.2

365 p21遺伝子導入による分化/老化誘導を作用機構とした癌に対する新しい分子療法

門脇嘉彦, 藤原俊義, 香川俊輔, 片岡正文, 西崎正彦, 深澤拓也, 和久利彦, 日伝晶夫, 田中紀章

日本消化器外科学会雑誌 32 ( 2 ) 462 - 462 1999.2

MOLECULAR SURGERY FOR HUMAN COLORECTAL CANCER WITH TUMOR SUPPRESSOR p53 GENE TRANSFER

FUJIWARA Toshiyoshi, TANAKA Noriaki

Journal of Japan Surgical Society 99 ( 7 ) 463 - 468 1998.7

89 大腸癌に対するp53遺伝子発現アデノウイルスベクターを用いた遺伝子治療の開発(第52回日本消化器外科学会総会)

邵江華, 藤原俊義, 小川誠之, 深澤拓也, 日伝晶夫, 田中紀章

日本消化器外科学会雑誌 31 ( 6 ) 1413 - 1413 1998.6

389 p53遺伝子導入によるアポトーシスへのFas/APO-1(CD95)レセプター/リガンドシステムの関与(第52回日本消化器外科学会総会)

深澤拓也, 藤原俊義, 守本芳典, 邵江華, 西崎正彦, 日伝晶夫, 田中紀章

日本消化器外科学会雑誌 31 ( 6 ) 1490 - 1490 1998.6

アデノウイルスベクターを用いた肝類洞壁内皮細胞への遺伝子導入の試み

藤澤憲司, 斎藤信也, 岡田豊, 藤原俊義, 田中紀章

日本外科学会雑誌 99 423 - 423 1998.3

MOLECULAR THERAPY FOR HUMAN CANCER BY WILD-TYPE p53 GENE TRANSFER

FUJIWARA Toshiyoshi, TANAKA Noriaki

23 ( 3 ) 600 - 605 1997.11

III-A-4 食道扁平上皮癌における p21 と p53 の集積および apoptosis に関する検討(<特集>第50回日本食道疾患研究会)

濱田円, 猶本良夫, 藤原俊義, 羽井佐実, 上川康明, 田中紀章

日本消化器外科学会雑誌 30 ( 5 ) 1039 - 1039 1997.5

p53遺伝子導入によるがん治療の可能性 (特集p53の生理作用--その多様性の源に迫る)

藤原俊義, 香川俊輔, 西崎正彦

細胞工学 16 ( 4 ) 556 - 563 1997.4

230 サイトカイン拮抗物質からみた手術侵襲に対する宿主反応(<特集>第49回日本消化器外科学会総会)

岩垣博巳, 日伝晶夫, 宮宗秀明, 平本孔彦, 藤原俊義, 松原長秀, 斉藤信也, 田中紀章

日本消化器外科学会雑誌 30 ( 2 ) 438 - 438 1997.2

II-187 イレウスにて発症した腸回転異常を伴った右型傍十二指腸ヘルニアの1治験例(<特集>第48回日本消化器外科学会総会)

前田徹也, 佐々木寛, 江添弘, 藤原俊義

日本消化器外科学会雑誌 29 ( 6 ) 1549 - 1549 1996.6

63 食道扁平上皮癌における p21 の topological control と p53, Ki67 との関連(<特集>第48回日本消化器外科学会総会)

濱田円, 猶本良夫, 藤原俊義, 羽井佐実, 上川康明, 田中紀章

日本消化器外科学会雑誌 29 ( 6 ) 1308 - 1308 1996.6

207 血中IL-1 receptor antagonist (IL-1ra) 値からみた外科的重症感染症による病態 : SIRSの解析(<特集>第48回日本消化器外科学会総会)

岩垣博巳, 日伝晶夫, 堀木貞幸, 藤原俊義, 田中紀章

日本消化器外科学会雑誌 29 ( 6 ) 1344 - 1344 1996.6

I-G-2 食道癌における p53の発現と, p21及びApoptosis との関連についての検討(<特集>第49回食道疾患研究会)

濱田円, 猶本良夫, 藤原俊義, 上川康明, 田中紀章, 折田薫三

日本消化器外科学会雑誌 29 ( 4 ) 940 - 940 1996.4

S4-11 大腸癌に対する p53遺伝子発現アデノウイルスとDNA障害性抗癌剤を用いた遺伝子治療(<特集>第47回日本消化器外科学会総会)

小川誠之, 藤原俊義, 香川俊輔, 濱田円, 日伝晶夫, 合地明, 田中紀章, 折田薫三

日本消化器外科学会雑誌 29 ( 2 ) 241 - 241 1996.2

非小細胞肺癌におけるp53遺伝子導入による抗癌剤感受性誘導機構の解析 : 遺伝子治療への応用 : 癌遺伝子2

香川俊輔, 藤原俊義, 井上文之, 岡林孝弘, 五味慎也, 小川誠之, 保田立二, 田中紀章, 折田薫三, Roth Jack A

肺癌 35 ( 5 ) 624 - 624 1995.9

W7-8 食道扁平上皮癌における apoptosis と p53 蛋白および p21 蛋白の集積に関する検討(<特集>第46回日本消化器外科学会)

濱田円, 猶本良夫, 藤原俊義, 羽井佐実, 上川康明, 田中紀章, 折田薫三

日本消化器外科学会雑誌 28 ( 6 ) 1327 - 1327 1995.6

W1-7 消化器癌における徐放性 IL-2(IL-2 ミニペレット) を用いた siteーdirected immunotherapyの試み(<特集>第39回日本消化器外科学会総会)

松岡順治, 阪上賢一, 合地明, 井谷史嗣, 小野田正, 藤原俊義, 斉藤信也, 高須伸治, 松野剛, 貞森裕, 光岡晋太郎, 田中屋宏爾, 三好和也, 中川秀和, 小林直哉, 日下敏, 宇田征史, 藤原拓造, 折田薫三

日本消化器外科学会雑誌 25 ( 2 ) 331 - 331 1992.2

125. 同所性ブタ肝移植における温阻血障害に対する徐放性 SOD (SMA-SOD) の有用性(<特集>第35回日本消化器外科学会総会)

蓮岡英明, 阪上賢一, 高須伸治, 河村武徳, 内田晋, 大岩敏彦, 羽井佐実, 塩崎滋弘, 黒住陽一, 藤原拓造, 小野田正, 稲垣優, 藤原俊義, 仁熊健文, 小林直哉, 三好和也, 日下敏, 折田薫三

日本消化器外科学会雑誌 23 ( 2 ) 341 - 341 1990.2

180 ブタ同所性肝移植に対する 15-Deoxyspergualin (DSG) の免疫抑制効果(<特集>第31回日本消化器外科学会総会)

高瀬伸治, 坂上賢一, 森崎太, 見市登, 森末正博, 大岩敏彦, 稲垣優, 河村武徳, 内田晋, 羽井佐実, 藤原俊義, 松本剛昌, 中井肇, 斎藤信也, 合地明, 折田薫三

日本消化器外科学会雑誌 21 ( 2 ) 453 - 453 1988.2

22. 良性胆道疾患における胆管十二指腸端側吻合術と他術式との比較検討(<特集>第16回日本胆道外科研究会)

筒井信正, 北村元男, 文〓雄, 平本孔彦, 高石義浩, 藤原俊義, 赤在義浩, 赤松良彦, 森谷行利, 木村秀幸, 大原利憲, 広瀬周平, 片岡和男, 間野清志

日本消化器外科学会雑誌 21 ( 1 ) 183 - 183 1988.1

289 残胃の癌の臨床病理学的検討(<特集>第30回日本消化器外科学会総会)

藤原俊義, 広瀬周平, 片岡和男, 北村元男, 筒井信正, 大原利憲, 木村秀幸, 森谷行利, 赤松良彦, 赤在義浩, 高石義浩, 文〓雄, 平本孔彦, 間野清志

日本消化器外科学会雑誌 20 ( 6 ) 1427 - 1427 1987.6

358 大腸穿孔を伴った大腸癌症例の検討(<特集>第28回日本消化器外科学会総会)

木村秀幸, 藤原俊義, 高石義浩, 中山文夫, 野田卓男, 赤在義浩, 赤松良彦, 山本優, 大原利憲, 筒井信正, 広瀬周平, 北村元男, 片岡和男, 間野清志

日本消化器外科学会雑誌 19 ( 6 ) 1350 - 1350 1986.6

450 先天性総胆管拡張症手術例の検討(<特集>第28回日本消化器外科学会総会)

野田卓男, 筒井信正, 高石義浩, 藤原俊義, 中山文夫, 赤在義浩, 赤松良彦, 山本優, 木村秀幸, 大原利憲, 広瀬周平, 北村元男, 片岡和男, 間野清志

日本消化器外科学会雑誌 19 ( 6 ) 1397 - 1397 1986.6

380 胃癌大腸癌肝転移例に対する治療成績(<特集>第28回日本消化器外科学会総会)

大原利憲, 間野清志, 片岡和男, 北村元男, 広瀬周平, 筒井信正, 木村秀幸, 山本優, 赤松良彦, 赤在義浩, 中山文夫, 野田卓男, 藤原俊義, 高石義浩

日本消化器外科学会雑誌 19 ( 6 ) 1362 - 1362 1986.6

547 胃癌治癒切除後における腹壁再発例の検討 : とくに再発後長期生存例について(<特集>第27回日本消化器外科学会総会)

中山文夫, 間野清志, 片岡和男, 北村元男, 広瀬周平, 筒井信正, 大原利憲, 木村秀幸, 山本優, 赤松良彦, 赤在義浩, 野田卓男, 藤原俊義, 高石義浩

日本消化器外科学会雑誌 19 ( 2 ) 527 - 527 1986.2

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